Culture

Philadelphia, June 30, 2020 - Auditory hallucinations, a phenomenon in which people hear voices or other sounds in the absence of external stimuli, are a feature of schizophrenia and some other neuropsychiatric disorders. How they arise in the brain has been unclear, but new research indicates that altered brain connectivity between sensory and cognitive processing areas may be responsible.

The study from researchers led by Stephan Eliez, MD, PhD, at Geneva University, Switzerland, appears in Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, published by Elsevier.

"Our results demonstrate aberrant development of the thalamic nuclei involved in sensory processing and [an] immature pattern of thalamo-cortical connectivity to the brain's auditory regions," said lead author Valentina Mancini, MD.

Using magnetic resonance imaging (MRI), the researchers compared brain structures and their connectivity in 110 healthy control subjects and in 120 subjects with a genetic disorder, named 22q11.2 deletion syndrome, or DS. People with 22q11.2 DS are at far higher risk than the general public to develop schizophrenia and to experience sensory hallucinations. An estimated one percent of people with schizophrenia have this disorder.

Abnormalities in the thalamus, a brain region recognized as the "gateway" for sensory information coming into the brain, had already been implicated in schizophrenia and hallucinations. In the current study, the authors sought to parse more specifically how the thalamus and its connections to other brain areas differed in people with 22q11.2 DS - with and without auditory hallucinations (AH) - from the control group. For this longitudinal study, the researchers collected brain scans every three years from subjects aged 8 to 35, with each receiving between 1 and 4 scans.

While neither the total volume of the thalamus nor its developmental growth trajectory differed between 22q11.2 DS and control subjects, the researchers found differences in specific thalamic sub-nuclei. The medial and lateral geniculate nuclei (MGN, LGN), which are involved in relaying auditory and visual sensory information, were smaller in people with 22q11.2 DS. In contrast, thalamic nuclei that communicate with the frontal cortex, which is involved in higher cognitive functions, were larger in 22q11.2 DS subjects than in healthy controls. In addition, other thalamic nuclei developed differently in the two groups.

When comparing 22q11.2 DS subjects with and without AH, those with AH had a smaller volume of MGN and a different developmental trajectory.

Upon assessing functional connectivity within the brain, the authors also found that subjects with AH had greater connectivity between MGN with the auditory cortex and other language-processing areas. They postulate that such hyper-connectivity might underlie the activation of such auditory areas at rest, leading to hallucinations.

"These findings provide a mechanistic explanation to the extreme likelihood of hallucinatory phenomena in youths prone to psychosis due to 22q11.2 deletion syndrome," Dr. Mancini added. "Further, the investigation of the developmental interactions between the thalamus and the cortex may help to identify new targets for intervention aimed at preventing the emergence of psychotic symptoms in individuals at-risk due to genetic conditions or clinical ultra-high-risk status."

Cameron Carter, MD, Editor of Biological Psychiatry: Cognitive Neuroscience and Neuroimaging added: "This study of individuals with 22q11 may provide a unique window into the alterations in brain development that underlie the development of psychotic symptoms, as well as other developmental and cognitive problems in these young people."

A multidisciplinary team from two Johns Hopkins University institutions, including neurotoxicologists and virologists from the Bloomberg School of Public Health and infectious disease specialists from the school of medicine, has found that organoids (tiny tissue cultures made from human cells that simulate whole organs) known as "mini-brains" can be infected by the SARS-CoV-2 virus that causes COVID-19.

The results, which suggest that the virus can infect human brain cells, were published online June 26, 2020, in the journal ALTEX: Alternatives to Animal Experimentation.

Early reports from Wuhan, China, the origin of the COVID-19 pandemic, have suggested that 36% of patients with the disease show neurological symptoms, but it has been unclear whether or not the virus infects human brain cells. In their study, the Johns Hopkins researchers demonstrated that certain human neurons express a receptor, ACE2, which is the same one that the SARS-CoV-2 virus uses to enter the lungs. Therefore, they surmised, ACE2 also might provide access to the brain.

When the researchers introduced SARS-CoV-2 virus particles into a human mini-brain model, the team found -- for what is believed to be the first time -- evidence of infection by and replication of the pathogen.

The human brain is well-shielded against many viruses, bacteria and chemical agents by the blood-brain barrier, which in turn, often prevents infections of the brain. "Whether or not the SARS-CoV-2 virus passes this barrier has yet to be shown," notes senior author Thomas Hartung, M.D., Ph.D., chair for evidence-based toxicology at the Bloomberg School of Public Health. "However, it is known that severe inflammations, such as those observed in COVID-19 patients, make the barrier disintegrate."

The impermeability of the blood-brain barrier, he adds, also can present a problem for drug developers targeting the brain.

The impact of SARS-CoV-2 on the developing brain is another concern raised by the study. Previous research from Paris-Saclay University has shown that the virus crosses the placenta, and embryos lack the blood-brain barrier during early development. "To be very clear," Hartung says, "we have no evidence that the virus produces developmental disorders."

However, the mini-brains -- which model the growing human brain -- contain the ACE2 receptor from their earliest stages of development. Therefore, Hartung says, the findings suggest that extra caution should be taken during pregnancy.

"This study is another important step in our understanding of how infection leads to symptoms, and where we might tackle the COVID-19 disease with drug treatment," says William Bishai, M.D., Ph.D., professor of medicine at the Johns Hopkins University School of Medicine, and leader of the infectious disease team for the study.

The human stem cell-derived mini-brain models -- known as BrainSpheres -- were developed at the Bloomberg School of Public Health four years ago. They were the first mass-produced, highly standardized organoids of their kind, and have been used to model a number of diseases, including infections by viruses such as Zika, dengue and HIV.

ATHENS, Ohio (June 30, 2020) - The South Pole has been warming at more than three times the global average over the past 30 years, according to research led by Ohio University professor Ryan Fogt and OHIO alumnus Kyle Clem.

Fogt, professor of meteorology and director of the Scalia Laboratory for Atmospheric Analysis, and Clem coauthored a paper with an international team of scientists published in the journal Nature Climate Change on the findings. According to the study, this warming period was mainly driven by natural tropical climate variability and was likely intensified by increases in greenhouse gas.

Clem, a current postdoctoral research fellow in climate science at Victoria University of Wellington in New Zealand, is the lead author of the study and studied under Fogt for both his bachelor's and master's degrees at Ohio University.

"I've had a passion for understanding the weather and fascination of its power and unpredictability as far back as I can remember," Clem said. "Working with Ryan I learned all about Antarctic and Southern Hemisphere climate, specifically how West Antarctica was warming and its ice sheet was thinning and contributing to global sea level rise. I also learned that Antarctica experiences some of the most extreme weather and variability on the planet, and due to its remote location we actually know very little about the continent, so there are constant surprises and new things to learn about Antarctica every year."

The Antarctic climate exhibits some of the largest ranges in temperature during the course of the year, and some of the largest temperature trends on the planet, with strong regional contrasts. Most of West Antarctica and the Antarctic Peninsula experienced warming and ice-sheet thinning during the late 20th century. By contrast, the South Pole -- located in the remote and high-altitude continental interior -- cooled until the 1980s and has since warmed substantially. These trends are affected by natural and anthropogenic climate change, but the individual contribution of each factor is not well understood.

Clem and his team analyzed weather station data at the South Pole, as well as climate models to examine the warming in the Antarctic interior. They found that between 1989 and 2018, the South Pole had warmed by about 1.8 degrees Celsius over the past 30 years at a rate of +0.6 degrees Celcius per decade - three times the global average.

The study also found that the strong warming over the Antarctic interior in the last 30 years was mainly driven by the tropics, especially warm ocean temperatures in the western tropical Pacific Ocean that changed the winds in the South Atlantic near Antarctica and increased the delivery of warm air to the South Pole. They suggest these atmospheric changes along Antarctica's coast are an important mechanism driving climate anomalies in its interior.

Clem and Fogt argue that these warming trends were unlikely the result of natural climate change alone, emphasizing the effects of added anthropogenic warming on top of the large tropical climate signal on Antarctic climate have worked in tandem to make this one of the strongest warming trends worldwide.

"From the very beginning, Kyle and I worked very well together and were able to accomplish more as a team than we were individually," Fogt said. "We have published every year together since 2013, with one of our continuing collaborations being the annual State of the Climate reports. Our work on this project together each year ultimately led to this publication documenting the warming at the South Pole, however, most importantly for me, apart from being a fantastic scientist and collaborator, my family and I are both honored to consider Kyle one of our closest friends."

Chanterelles (Cantharellus cibarius) are one of the most popular mushrooms in Germany. Depending on the weather, chanterelle season starts in early July. Connoisseurs value the mushroom's delicate fruity aroma, which is reminiscent of apricots, and its aromatic and slightly bitter taste profile. Not only do chanterelles have a unique flavor profile, they also function as taste enhancers, lending dishes a well-rounded mouthfeel and a lingering, rich flavor.

Key substances for the kokumi sensation

"Using the ultra-high-performance liquid chromatography-mass spectrometry method developed by our team, we are now the first to accurately quantify the key substances in chanterelles that are responsible for the kokumi effect", says Dr. Verena Mittermeier from the TUM Chair of Food Chemistry and Molecular Sensory Science. Dr. Verena Mittermeier already contributed significantly to the study during her time as a PhD student under Prof. Thomas Hofmann, who now serves as the President of TUM.

As the research team's findings show, the effect is caused by natural substances derived from fatty acids. Storage conditions, such as duration of storage and temperature, affect the composition and concentration of these fatty acid derivatives in the mushrooms. Whether the mushrooms are stored whole or chopped also plays a role.

New quality control marker

According to food chemist Andreas Dunkel from the Leibniz-Institute for Food Systems Biology at the Technical University of Munich, some of these derivatives are specific to chanterelles and can therefore be used as markers to control the quality of mushroom products. These findings could also be used to systematically improve the flavor profile of mushroom dishes or other savoury dishes using natural substances.

Andreas Dunkel explains: "Kokumi is a Japanese word that does not refer to a specific flavor quality such as salty or sweet." Instead, the fatty acid derivatives modulate the sensory characteristics of other ingredients.

The database comprises information on the so-called "ground reaction force" (GRF) which is the force between the foot and the ground that is generated during movement. It is an important standard parameter used in clinical practice and in research. The figures form the basis for diagnosis and for the assessment of therapeutic success.

"Gait analysis provides a huge amount of data. Their interpretation is challenging and there is a great deal of interest in supporting medical decision-making processes with machine learning methods. The more data we have, the better the results", explains Brian Horsak, head of the research focus Motor Rehabilitation at the St. Pölten UAS.

Anonymised Data of More than 2,000 Patients

In order to facilitate research, therapy and diagnosis, Brian Horsak and his colleagues at the St. Pölten UAS and the AUVA have now published one of the biggest data records worldwide on this topic in anonymised form. The data include anonymised information on more than 2,000 patients after joint transplantations, fractures and ligament injuries as well as associated impairments of the hips, knees, ankles and heel bones.

The data come from several years of clinical gait analysis practice and can be used to improve analysis procedures and models. The database called "GAITREC" is available online free of charge.

"We have processed and published the data together with the AUVA. In times of the coronavirus, this dataset is even more interesting as many experts are unable to collect data in the lab and therefore have to rely on existing data records. Our dataset can be of assistance here, in terms of both teaching and research", emphasises Djordje Slijepčevi?, co-author of "GaitRec" and machine learning expert at the St. Pölten UAS.

Research Focus Motor Rehabilitation

The research focus Motor Rehabilitation at the St. Pölten UAS develops technology-assisted approaches to physical rehabilitation and promotes their widespread application in clinical practice through collaborations with partners. Within the framework of this research focus, the St. Pölten UAS and the AUVA have been carrying out joint research projects for years.

These last couple of years, the St. Pölten UAS has expanded its competencies in the fields of motor rehabilitation, instrumented 3D gait and movement analysis, machine learning, visual analytics, and augmented & virtual reality, and anchored them on location in the Center for Digital Health Innovation (CDHI). With the Digital Health Lab, the UAS has one of the most modern research labs in Austria in these fields.

The technical advancements in the aforementioned areas open up new and innovative treatment options in physical rehabilitation far beyond the existing approaches. The described works on the GAITREC database were partly funded by NÖ Forschungs- und Bildungsges.m.b.H. (NFB) and the department of science and research of the Lower Austrian state government.

EAST HANOVER, NJ - June 30, 2020 - On a June 24 webinar, titled, "The ADA Generation: A Dialogue with Recent College Graduates with Disabilities," experts in employment and disability engaged with three young professionals to relate the results of a new national survey to the real-world experiences of recent college graduates with disabilities. The survey, commissioned by Kessler Foundation and implemented by the University of New Hampshire Institute on Disability (UNH-IOD), commemorates the 30th anniversary of the Americans with Disabilities Act (ADA) of 1990, and explores its impact on the first generation to come of age since the ADA's passage in 1990.

The panel focused on the topline findings of the 2020 Kessler Foundation National Employment and Disability Survey: Recent College Graduates, the third in a series of surveys that are changing perceptions about disability and work, and establishing new pathways for greater inclusion of people with disabilities in the workplace. The overall results of the 2020 survey were presented nationally on June 3, 2020 via a Zoom webinar, titled, "The ADA Generation: New Perspectives on Employment and College Graduates with Disabilities," and via a EurekAlert release. The experts reported that college students with disabilities were taking advantages of career services during college, and were transitioning from college to work at the same rate as their peers without disabilities - 90%.

Economist Andrew Houtenville, PhD, of UNH-IOD chaired the June 24 webinar, which featured John O'Neill, PhD, director of the Center for Employment and Disability at Kessler Foundation, Kimberly Phillips, PhD, of UNH-IOD, and psychologist Elizabeth Cardoso, PhD, chair of the Educational Foundations and Counseling Programs at Hunter College-City University of New York. Dr. Cardoso related the survey's new findings to the outcomes of the MIND Alliance grant she received from the National Science Foundation. MIND Alliance fosters careers in Science, Technology, Engineering, and Mathematics (STEM) among minority students with disabilities in high school, community college and college.

The college graduates with disabilities who shared their experiences were Hieu Duc Dang, AA, BA, MS, benefits counselor at the Center for Independence of the Disabled (CIDNY), Bryce Stanley, BA, MS, PhD candidate, research assistant at the University of New Hampshire, and Annemarie Veira, BA, MS, CRC, coordinator of the Office of Disability Resources at of the School of Visual Arts in New York City.

The 2020 survey collected a wealth of information, including details of college majors and occupations, finding that students with disabilities were more likely to pursue career paths focused on helping people, and less likely to choose STEM majors, or to work in STEM disciplines. "Preparing for STEM careers will help people with disabilities take advantage of this growth sector in our economy," said Dr. O'Neill. "Research shows that this is a disparity that can be addressed with the right support system," he added.

Providing comprehensive support beginning in high school can increase the participation of minorities with disabilities in STEM careers, according to Dr. Cardoso. "More than 700 students received the services of the MIND Alliance," she reported, "including role modeling, tutoring, and mentoring, as well as exposure to internships, exposure to careers in STEM, and exposure to individuals with disabilities in STEM careers. These MIND Alliance students excelled in terms of their graduation rates at every level, in transitioning to higher education, and in choosing STEM careers."

During the webinar, Dang, Stanley and Veira shared how their college experiences compared with the survey's main findings, in terms of disability and career services, accommodations, and preparation for transitioning to the workplace. They were encouraged when the survey showed that peers with disabilities were striving to work and transitioning to jobs as they had, but cautioned that there are still disparities in job quality (e.g., earnings, hours working) between college graduates with and without disabilities.

"We've learned a great deal from the survey and our panelists," Dr. O'Neill acknowledged. "We plan to look deeper into our results to find better ways to support and advise youth with disabilities, their families, and educators. Looking at the impact of the type of disability and the type of college, for example, will yield useful information," he predicted. It's clear that we can build on the gains that individuals with disabilities have made since the ADA, and improve their educational experience and employment outcomes."

For the first time, researchers in the lab of CSHL Professor Hiro Furukawa have been able to track each atom in the NMDA receptor, an important brain protein, as it transmits or inhibits neural signals. Critical for brain development and function, the receptor converts chemical messages between cells into electrical signals within a neuron. The key to transmitting that information is opening the receptor's built-in ion channel, a hollow pore that allows electrically charged ions to flow. Unlocking the receptor's ion channel is like working a stringed puppet--rock one part of the receptor and slender filaments pull open the channel's gate. Rock it a little differently, the filaments loosen, and the gate snaps shut. Understanding how the receptor works could lead to better treatments for Alzheimer's disease, depression, epilepsy, stroke, or schizophrenia.

Using high resolution electron cryo-microscopy (cryo-EM) and a series of specially constructed receptors, the scientists were able to follow every twist and turn of receptor parts as they bind natural and synthetic compounds, rock open the gate, and let it shut again.

The NMDA receptor is embedded in the neuronal membrane with the receptor binding portion on the outside of the cell and the ion channel spanning the cell membrane. When activating molecules glycine and glutamic acid bind to the ligand-binding domain (LBD) in the right way, the LBD rocks, pulling a loop or filament attached to the ion channel gate to open it. But if an antagonist binds, the loop loosens so much that the LBD cannot pull open the gate. Furukawa says:

"This is all happening because the subunit arrangement changes quite dramatically upon binding to the inhibitor. It all comes down to the stretching and non-stretching of the loop between the ligand-binding domain and the ion channel. They're really a series of conformations or events that are happening outside [the cell], and it eventually gets translated to the ion channel activity,"

Formerly, the stretching of the loops and their effect on the opening and closing of the ion channel were pure speculation on Furukawa's part. Now he has the data to prove what before he could only imagine.

Watch "How does the NMDA receptor work?": https://www.youtube.com/watch?v=5zqBsPmH8ck

There are multiple conformations when glycine and glutamate are bound to NMDA receptor's Ligand Binding Domain (LBD). In going from non-active to active state, there is going to be a rolling motion--I'm going to go back again--there's going to be a rolling motion of Ligand Binding Domain. Here is the loop that tethers Ligand Binding Domain and a transmembrane domain. And the transmembrane domain forms the ion channel pore. When this rolling motion happens, it is that the loop that tethers that transmembrane domain would be stretched. When the loop is stretched, what happens is that the residues, or amino acids, that are forming the ion channel pore is stretched apart.

This discovery will enable researchers to develop better drugs to control the NMDA receptor's activity, which can be involved in Alzheimer's disease, depression, schizophrenia, stroke, and epilepsy. The insights gained in this study may also be applicable to other receptor-mediated ion channels.

Measurements from NASA's Transiting Exoplanet Survey Satellite (TESS) have enabled astronomers to greatly improve their understanding of the bizarre environment of KELT-9 b, one of the hottest planets known.

"The weirdness factor is high with KELT-9 b," said John Ahlers, an astronomer at Universities Space Research Association in Columbia, Maryland, and NASA's Goddard Space Flight Center in Greenbelt, Maryland. "It's a giant planet in a very close, nearly polar orbit around a rapidly rotating star, and these features complicate our ability to understand the star and its effects on the planet."

The new findings appear in a paper led by Ahlers published on June 5 in The Astronomical Journal.

Located about 670 light-years away in the constellation Cygnus, KELT-9 b was discovered in 2017 because the planet passed in front of its star for a part of each orbit, an event called a transit. Transits regularly dim the star's light by a small but detectable amount. The transits of KELT-9 b were first observed by the KELT transit survey, a project that collected observations from two robotic telescopes located in Arizona and South Africa.

Between July 18 and Sept. 11, 2019, as part of the mission's yearlong campaign to observe the northern sky, TESS observed 27 transits of KELT-9 b, taking measurements every two minutes. These observations allowed the team to model the system's unusual star and its impact on the planet.

KELT-9 b is a gas giant world about 1.8 times bigger than Jupiter, with 2.9 times its mass. Tidal forces have locked its rotation so the same side always faces its star. The planet swings around its star in just 36 hours on an orbit that carries it almost directly above both of the star's poles.

KELT-9 b receives 44,000 times more energy from its star than Earth does from the Sun. This makes the planet's dayside temperature around 7,800 degrees Fahrenheit (4,300 C), hotter than the surfaces of some stars. This intense heating also causes the planet's atmosphere to stream away into space.

Its host star is an oddity, too. It's about twice the size of the Sun and averages about 56 percent hotter. But it spins 38 times faster than the Sun, completing a full rotation in just 16 hours. Its rapid spin distorts the star's shape, flattening it at the poles and widening its midsection. This causes the star's poles to heat up and brighten while its equatorial region cools and dims -- a phenomenon called gravity darkening. The result is a temperature difference across the star's surface of almost 1,500 F (800 C).

With each orbit, KELT-9 b twice experiences the full range of stellar temperatures, producing what amounts to a peculiar seasonal sequence. The planet experiences "summer" when it swings over each hot pole and "winter" when it passes over the star's cooler midsection. So KELT-9 b experiences two summers and two winters every year, with each season about nine hours.

"It's really intriguing to think about how the star's temperature gradient impacts the planet," said Goddard's Knicole Colón, a co-author of the paper. "The varying levels of energy received from its star likely produce an extremely dynamic atmosphere."

KELT-9 b's polar orbit around its flattened star produces distinctly lopsided transits. The planet begins its transit near the star's bright poles and then blocks less and less light as it travels over the star's dimmer equator. This asymmetry provides clues to the temperature and brightness changes across the star's surface, and they permitted the team to reconstruct the star's out-of-round shape, how it's oriented in space, its range of surface temperatures, and other factors impacting the planet.

"Of the planetary systems that we've studied via gravity darkening, the effects on KELT-9 b are by far the most spectacular," said Jason Barnes, a professor of physics at the University of Idaho and a co-author of the paper. "This work goes a long way toward unifying gravity darkening with other techniques that measure planetary alignment, which in the end we hope will tease out secrets about the formation and evolutionary history of planets around high-mass stars."

Changes in blood platelets triggered by COVID-19 could contribute to the onset of heart attacks, strokes, and other serious complications in some patients who have the disease, according to University of Utah Health scientists. The researchers found that inflammatory proteins produced during infection significantly alter the function of platelets, making them "hyperactive" and more prone to form dangerous and potentially deadly blood clots.

They say better understanding the underlying causes of these changes could possibly lead to treatments that prevent them from happening in COVID-19 patients. Their report appears in Blood, an American Society of Hematology journal.

"Our finding adds an important piece to the jigsaw puzzle that we call COVID-19," says Robert A. Campbell, Ph.D., senior author of the study and an assistant professor in the Department of Internal Medicine. "We found that inflammation and systemic changes, due to the infection, are influencing how platelets function, leading them to aggregate faster, which could explain why we are seeing increased numbers of blood clots in COVID patients."

Emerging evidence suggests COVID-19 is associated with an increased risk of blood clotting, which can lead to cardiovascular problems and organ failure in some patients, particularly among those with underlying medical problems such as diabetes, obesity, or high blood pressure.

To find out what might be going on, the researchers studied 41 COVID-19 patients hospitalized at University of Utah Hospital in Salt Lake City. Seventeen of these patients were in the ICU, including nine who were on ventilators. They compared blood from these patients with samples taken from healthy individuals who were matched for age and sex.

Using differential gene analysis, the researchers found that SARS-CoV-2, the virus that causes COVID-19, appears to trigger genetic changes in platelets. In laboratory studies, they studied platelet aggregation, an important component of blood clot formation, and observed COVID-19 platelets aggregated more readily. They also noted that these changes significantly altered how platelets interacted with the immune system, likely contributing to inflammation of the respiratory tract that may, in turn, result in more severe lung injury.

Surprisingly, Campbell and his colleagues didn't detect evidence of the virus in the vast majority of platelets, suggesting that it could be promoting the genetic changes within these cells indirectly.

One possible mechanism is inflammation, according to Bhanu Kanth Manne, Ph.D., one of the study's lead authors and a research associate with the University of Utah Molecular Medicine Program (U2M2). In theory, inflammation caused by COVID-19 could affect megakaryocytes, the cells that produce platelets. As a result, critical genetic alterations are passed down from megakaryocytes to the platelets, which, in turn, make them hyperactive.

In test tube studies, the researchers found that pre-treating platelets from SARS-CoV-2 infected patients with aspirin did prevent this hyperactivity. These findings suggest aspirin may improve outcomes; however, this will need further study in clinical trials. For now, Campbell warns against using aspirin to treat COVID-19 unless recommended by your physician.

In the meantime, the researchers are beginning to look for other possible treatments.

"There are genetic processes that we can target that would prevent platelets from being changed," Campbell says. "If we can figure out how COVID-19 is interacting with megakaryocytes or platelets, then we might be able to block that interaction and reduce someone's risk of developing a blood clot."

"Clean margins" are a goal of cancer excision surgery. If even a small piece of cancerous tissue is left behind, it increases the likelihood of a local recurrence and spread of the disease, possibly reducing overall survival time.

With an innovative approach to cancer surgery, researchers at the University of Pennsylvania are investigating a technique to help surgeons clearly see whether they've left any diseased tissue behind. Using a dye that glows under near-infrared light and preferentially accumulates in cancer cells, they performed surgery to remove mammary tumors from dogs treated at the School of Veterinary Medicine's Ryan Hospital.

They found that the technique was able to illuminate not only the tumors but also cancer that had spread to the lymph nodes. Mammary cancer in dogs is akin to human breast cancer in many key ways. The research team believes that, with a different dye that is more specifically targeted to cancer cells, a parallel technique could improve outcomes in breast cancer patients who opt for breast-conserving surgery to treat their disease, The researchers reported this in the journal PLOS ONE.

"Doing this kind of research has two main benefits," says David Holt, a veterinary surgeon and senior author on the work. "The dogs are a great model for human breast cancer, but there are also some real opportunities to benefit the dogs as well."

A team from Perelman School of Medicine led by Sunil Singhal of the Center for Precision Surgery at the Abramson Cancer Center in collaboration with Holt and others at Penn Vet have been using the FDA-approved contrast agent indocyanine green (ICG), which glows under near-infrared light, to attempt to differentiate normal from cancerous tissue for several years in different types of cancer. Scientists believe ICG accumulates in cancer because it leaks out through the fast-growing blood vessels in tumors, which tend to be more permeable than normal vessels in healthy tissue.

The aim of the current work was to test the technique in pet dogs with mammary tumors as a model for breast conserving surgery in women. All pet owners gave consent to be part of the study. The day before surgery, dogs received an injection of ICG. The surgeries themselves, either lumpectomies or mastectomies, proceeded as they normally would, following standard-of-care procedures. Then, under near-infrared light, the surgeons observed the excised tumors as well as the surgical site to look for signs of glowing ICG.

In dogs, since aesthetics are less of a concern, surgeons generally take much wider margins when excising mammary tumors than is done when performing breast-conserving surgery on a person. So, the study wasn't able to detect remnant "dirty edges" after excision. They did, however, find larger tumors accumulated more dye.

The research team was also interested in looking at the dogs' lymph nodes.

"In women with breast cancer and also in dogs with mammary cancer," Holt says, "it's prognostic if the cancer has spread to the lymph nodes. What we showed was that we could identify both draining lymph nodes and lymph nodes with metastatic disease."

Currently in human medicine, radioisotopes administered into the breast are often used to identify draining or "sentinel" lymph nodes. Using a near-infrared imaging agent administered intravenously means that radioactive agent and the protective shielding that it necessitates are not required.

"If we could give an injection before the surgery that would identify just the lymph nodes that are potentially problematic, it would avoid a lot of the risk of either removing too many lymph nodes or leaving in those that are have metastatic disease," says Holt.

In concurrent and follow-up work, Holt and his counterparts at Penn Medicine are continuing to investigate the efficacy of using targeted near-infrared imaging agents in cancer patients. These dyes bind more specifically to cancer cells, helping better define "clean margins" for both human and canine cancer patients.

As the world wrestles with the coronavirus (COVID-19) pandemic, which arose after the virus jumped from an animal species to the human species, University of Delaware researchers are learning about new ways other pathogens are jumping from plants to people.

Opportunistic bacteria -- salmonella, listeria and E. coli, for example -- often piggyback on raw vegetables, poultry, beef and other foods to gain entry into a human host, causing millions of foodborne illnesses each year.

But University of Delaware researchers Harsh Bais and Kali Kniel and their collaborators now have found that wild strains of salmonella can circumvent a plant's immune defense system, getting into the leaves of lettuce by opening up the plant's tiny breathing pores called stomates.

The plant shows no symptoms of this invasion and once inside the plant, the pathogens cannot just be washed off.

Stomates are little kidney-shaped openings on leaves that open and close naturally and are regulated by circadian rhythm. They open to allow the plant to cool off and breathe. They close when they detect threats from drought or plant bacterial pathogens.

Some pathogens can barge into a closed stomate using brute force, Bais said. Fungi can do that, for example. Bacteria don't have the enzymes needed to do that so they look for openings -- in roots or through stomates, he said.

Plant bacterial pathogens have found a way to reopen those closed stomates and gain entry to the plant's internal workings, Bais said.

But now, in research published by Frontiers in Microbiology, Bais and Kniel have shown that some strains of the human pathogen salmonella have developed a way to reopen closed stomates, too.

"What's new is how the non-host bacteria are evolving to bypass plant immune response," Bais said. "They are real opportunists. They are absolutely jumping kingdoms....When we see these unusual interactions, that's where it starts to get complex."

Opportunities for pathogens arise as plants are bred to increase yield, often at the expense of their own defense systems. Other opportunities arise when a grower plants low-lying crops too close to a livestock field, making contamination easier.

Together and separately, Bais and Kniel and their collaborators have been looking at this plant problem from several angles for about five years.

They are looking at the "trojan horse" methods bacteria such as salmonella are using to elude plant immune systems and find their way to new human hosts.

They are looking at an assortment of irrigation methods that can carry bacteria from waterways, ponds and reclaimed water to the surface and root systems of plants.

They are looking at the genetic components that enable pathogens to persist and survive along their passage to a new host.

Bais and Kniel have published multiple articles on these threats to the world's food supply and have developed recommendations for increasing plant defenses.

Bais' team, for example, developed and patented a beneficial microbe -- UD1022 -- to protect and strengthen plant root systems. That microbe has been licensed by BASF and is incorporated into an increasing variety of applications. Testing done as part of their new publication showed that roots inoculated with UD1022 -- through watering and irrigation -- could provide protection from these opportunistic bacteria.

Kniel said she was surprised to see that UD1022 kept some mutants from getting into the plant.

"There is a lot of hope for biocontrols," she said.

Kniel's team and collaborators from the U.S. Department of Agriculture and several other universities in the Mid-Atlantic region, recently published new findings in PLOS One analyzing the pathogenic content of irrigation methods that draw from waterways, ponds and reclaimed water.

Those are pre-harvest perils. The post-harvest dangers come more from hygiene practices of workers on the conveyor belts that move these products to market.

Many companies run leafy greens through water treated with appropriate sanitizers and may consider ozone or ultraviolet treatments to address surface bacteria. They can't see or treat human pathogens that already have gotten into the leaf.

"The food industry works tirelessly to make the product as safe as they can," Kniel said. "But even then, we are growing these products outside, so they're accessible to wildlife, wind, dust and water that may transmit microorganisms. It's a tough situation."

Nicholas Johnson, a graduate student in Bais' lab, did painstaking work to examine how stomates on spinach and lettuce responded to applications of salmonella, Listeria and E. coli -- three human pathogens that leave no apparent fingerprints, no way to see that they have infected a plant. He recorded the size of the stomate openings -- called the aperture -- for hundreds of stomates on each sample leaf.

He counted these sizes every three hours after the bacteria were applied.

"He had to sit under a microscope and count the aperture sizes," Bais said. "And he has to be meticulous."

He found some troubling results. The salmonella strain was reopening the stomates.

"Now we have a human pathogen trying to do what plant pathogens do," Bais said. "That is scary."

It would be especially scary, Bais said, if it were to occur in a "vertical" farm, where plants are grown in vertical rows hydroponically.

"These are wonderful systems," Kniel said. "But there needs to be a lot of care within the system to control the water and interactions with people. There has to be a lot of handwashing. I work with a lot of growers to make sure they have 'clean' breaks and are sanitizing properly. When you do that, you have fewer products to recall."

But the dangers are real.

"The industry is working hard on this," Kniel said. "They are some of the most passionate, dedicated people I have ever met. But outbreaks happen."

"And if this hits vertical farms, they don't lose a batch," Bais said. "They lose the whole house."

The collaboration has drawn on a wide range of expertise, giving researchers insight into many angles of the problem.

"This project [with Bais] has mutant salmonella strains and that allows us another angle on the molecular biology side," Kniel said. "The individual mutations are important for the salmonella structure and the regulation of stress. We can see the ability of the salmonella to internalize into the plant. When we used mutant strains we saw big differences in the ability to colonize and internalize -- and that's what consumers hear a lot about. You are not able to wash it off.

"We can also look at which genes or part of the organism might be more responsible for the persistence on the plant - making it last longer and stronger. That is so important when you think of food safety issues."

Among the other questions researchers are asking:

Do these bacteria die off more easily when they are in the sun?

Does a lot of moisture or humidity allow them to grow?

How much do they interact with the plant?

The study of irrigation water in the Mid-Atlantic region of the United States was done in collaboration with "Conserve," a Center of Excellence that includes researchers from the U.S. Department of Agriculture and the University of Maryland.

"We're looking at where growers get their water from and what they are doing to make sure it is microbially safe," she said.

Some of the water is reclaimed after it was used to wash other crops. Some comes from waterways and ponds. The team took a series of samples over a two-year period, testing for salmonella, listeria, E. coli, viruses and protozoa.

"Water has been shown in multiple outbreaks to be a potential risk of contamination," Kniel said. "This paper is important because it is identifying the risks of ponds, rivers and reclaimed water as well as discussing what growers could do and how to treat water. A lot of growers are happy to use the technology as long as it is cost-effective and reliable and can be used for fresh produce."

All life depends on a genome, which acts as an instruction manual for building all the products essential for development and survival. But knowing which of these individual instructions - or genes - need to be read, and when, is key for a properly functioning organism: so how does life get this right?

Enter epigenetic regulation - the process by which cells control the expression, or readability, of genes. In multicellular organisms, epigenetics is the reason why every type of cell varies in shape and function, with each cell type following a different subset of instructions. Cells also use epigenetic regulation as an 'immune system', suppressing the activity of disruptive 'jumping genes' called transposons that can otherwise hop around the genome and threaten its integrity.

Despite its importance, scientists are still struggling to untangle the many pathways that cells use to precisely control the activity of genes. Now, researchers from the Okinawa Institute of Science and Technology Graduate University (OIST) have uncovered a clue to the mystery, by looking at how plant cells suppress transcription - the first stage of how genes manufacture their products. Their findings, recently published in Nature Communications, pinpoint previously unknown sections of DNA that are silenced by epigenetic regulation, many of which originate within transposons.

"This study provides a comprehensive view on how and where cells suppress transcription across the whole genome," said Dr. Tu Le, first author and postdoctoral researcher in the OIST Plant Epigenetics Unit. "Importantly, we found that this silencing was vital for ensuring that genes involved in development and stress responses function properly."

During transcription, cellular machinery copies a section of DNA into RNA. Usually, these RNA transcripts are then used to make proteins. Cells can boost or suppress transcription by adding chemical tags to DNA or to histone proteins that package the DNA, which tell the machinery which RNA transcripts - and ultimately proteins - to produce and in what quantity.

This level of precise control is vital for managing transposons. "Transposons are parasites of genomes, that promote their own expression at the expense of the organism," said Professor Hidetoshi Saze, senior author of the study and leader of the Plant Epigenetics Unit. "When a transposon is active, its genetic sequence is used to manufacture a protein that can move the transposon to a different location in the genome, like cut-and paste or copy-and-paste computer functions."

Transposons are usually silenced, as their activity can disable important genes. But sometimes, when under stress, plants re-activate transposons as they are a source of genetic variation, potentially generating beneficial mutations that allow the plant to adapt to the changing environment.

"Our lab ultimately aims to determine exactly how cells recognize and regulate transposons," added Dr. Le. "This work is an important first step toward this goal."

Unveiling hidden sites of transcription

In the study, the scientists used several mutant strains of a plant called Arabidopsis thaliana, with a different epigenetic pathway disabled in each strain.

The team then used a sequencing technique to detect specific DNA sequences that act as starting sites for the genome's transcription machinery. They revealed thousands of these 'transcription start sites' (TSSs) that were only active in the epigenetic mutants.

"Many of these sites hadn't been detected in previous studies, because they are completely silenced in wildtype plants. Our discovery of these hidden - or cryptic - TSSs provides a valuable source of data for future epigenetic research in plants," said Prof. Saze.

The scientists identified one mutant strain of the plant that activated an especially high number of cryptic TSSs. The gene this mutant was missing encodes a key protein which maintains DNA methylation. When methyl groups are added to DNA, this epigenetic tag triggers a biochemical pathway that causes histones to pack the DNA more tightly. This physically stops transcription machinery from accessing the regions of the genome that contain the cryptic TSSs.

"The sheer number of cryptic TSSs activated when DNA methylation is lost shows that it is a powerful and prevalent method of silencing," said Dr. Le.

From transposons to stress tolerance

Another key finding was the link between transposons and cryptic TSSs. The scientists found that up to 65% of cryptic TSSs originated within these 'jumping genes', which were longer and more heavily methylated that transposons without cryptic TSSs.

"This suggests that transposons with cryptic TSSs are younger, intact and still able to jump around the genome, which is why they are silenced," explained Dr. Le.

Strikingly, the scientists noticed that when the cryptic TSSs were activated in the epigenetic mutants, this changed the activity of nearby genes involved in stress and development. The scientists don't yet fully understand the mechanism behind this impact, but the implications are intriguing.

"There is previous research that shows that over time, as transposons degrade, plants can adapt the TSSs in transposons for their own use, to regulate the activity of nearby genes," said Prof Saze. "The effect of the activated cryptic TSSs on stress and development genes suggests that in the future, plants could use these TSSs to adapt to changing conditions."

In future research, the scientists hope to learn more about these cryptic TSSs and how they affect the activity of nearby genes. "This study might help us to better understand how plants respond to environmental changes such as global warming, drought and nutrient degradation in soil. It may then be possible to develop new crops which are resistant to these kinds of stress," Prof. Saze said.

Experiments in mice have shown early success in vaccinating them against potentially deadly bacterial infections, such as methicillin-resistant Staphylococcal aureus, or MRSA, the strain resistant to most drug treatments.

The new vaccination strategy, developed by researchers at NYU Grossman School of Medicine, targets toxic molecules released by all Staphylococcal bacteria, called leukocidins, rather than directly targeting the bacteria.

Attempts to develop a Staphylococcal vaccine have so far failed, researchers say, in part because leukocidins kill immune system cells, or leukocytes, needed by the immune system to fight the infection and whose production is triggered by a vaccine. As a consequence, these bacteria release leukocidins to evade not only an immediate immune cell attack, but also to prevent the infected host, whether human or mouse, from developing any long-term immunity through antibodies, which are also produced by leukocytes.

Now, a new study publishing in the Journal of Experimental Medicine online June 30 finds that 70 percent of mice given the experimental vaccine targeting the leukocidins survived infections with the bacterium. By contrast, no infected mice survived without the vaccine.

Previous work by the same research team found that mice could survive infection with Staphylococcal bacteria whose leukocidins had been genetically modified to lose their toxic effects. These nontoxic leukocidins formed the basis of the experimental vaccine.

"Our study provides a roadmap for developing an effective vaccine against all Staphylococcal infections, especially MRSA," says study senior investigator Victor J. Torres, PhD, the C.V. Starr Professor of Microbiology at NYU Langone. "This strategy is based on maximum disarmament of the bacterium's ability to kill all types of immune system cells."

"By targeting the toxins released by the bacteria, our experimental vaccine not only stops the bacteria from killing neutrophils, a key type of leukocyte the immune system uses to destroy the invading pathogen, but also defends other leukocytes, such as T cells and B cells, needed to provide long-term protection from future infection," says Torres.

Among the key study results was that mice repeatedly infected with toxin-releasing Staphylococcal bacteria demonstrated an immune response to the infection, producing antibodies to both the bacteria and its leukocidins. However, mice infected with bacteria engineered to not produce the toxins had twice as many antibodies targeting the bacteria, showing a much stronger immune response when the toxins were absent. This heightened immune response is what researchers say led them to target leukocidins as the best possible means of giving those infected the "upper hand" in fighting the bacterium.

Torres cautions that a commercially available antileukocidin vaccine is years away. The next step for his team is clinical trials to investigate whether humans vaccinated against the toxins show a similar toxin-specific immune response as seen in the mice.

He says investigators also want to find out if the same antitoxin effects occur for any of the hundreds of other molecules released during Staphylococcal infections. Torres says a "foolproof" vaccine against the bacteria, including MRSA, will likely involve targeting more than just its leukocidin toxins.

The latest United States estimates are that more than 119,000 people suffered from Staphylococcal bloodstream infections in 2017, leading to nearly 20,000 deaths.

Using the European Southern Observatory's Very Large Telescope (VLT), astronomers have discovered the absence of an unstable massive star in a dwarf galaxy. Scientists think this could indicate that the star became less bright and partially obscured by dust. An alternative explanation is that the star collapsed into a black hole without producing a supernova. "If true," says team leader and PhD student Andrew Allan of Trinity College Dublin, Ireland, "this would be the first direct detection of such a monster star ending its life in this manner."

Between 2001 and 2011, various teams of astronomers studied the mysterious massive star, located in the Kinman Dwarf galaxy, and their observations indicated it was in a late stage of its evolution. Allan and his collaborators in Ireland, Chile and the US wanted to find out more about how very massive stars end their lives, and the object in the Kinman Dwarf seemed like the perfect target. But when they pointed ESO's VLT to the distant galaxy in 2019, they could no longer find the telltale signatures of the star. "Instead, we were surprised to find out that the star had disappeared!" says Allan, who led a study of the star published today in Monthly Notices of the Royal Astronomical Society.

Located some 75 million light-years away in the constellation of Aquarius, the Kinman Dwarf galaxy is too far away for astronomers to see its individual stars, but they can detect the signatures of some of them. From 2001 to 2011, the light from the galaxy consistently showed evidence that it hosted a 'luminous blue variable' star some 2.5 million times brighter than the Sun. Stars of this type are unstable, showing occasional dramatic shifts in their spectra and brightness. Even with those shifts, luminous blue variables leave specific traces scientists can identify, but they were absent from the data the team collected in 2019, leaving them to wonder what had happened to the star. "It would be highly unusual for such a massive star to disappear without producing a bright supernova explosion," says Allan.

The group first turned the ESPRESSO instrument toward the star in August 2019, using the VLT's four 8-metre telescopes simultaneously. But they were unable to find the signs that previously pointed to the presence of the luminous star. A few months later, the group tried the X-shooter instrument, also on ESO's VLT, and again found no traces of the star.

"We may have detected one of the most massive stars of the local Universe going gently into the night," says team-member Jose Groh, also of Trinity College Dublin. "Our discovery would not have been made without using the powerful ESO 8-metre telescopes, their unique instrumentation, and the prompt access to those capabilities following the recent agreement of Ireland to join ESO." Ireland became an ESO member state in September 2018.

The team then turned to older data collected using X-shooter and the UVES instrument on ESO's VLT, located in the Chilean Atacama Desert, and telescopes elsewhere."The ESO Science Archive Facility enabled us to find and use data of the same object obtained in 2002 and 2009," says Andrea Mehner, a staff astronomer at ESO in Chile who participated in the study. "The comparison of the 2002 high-resolution UVES spectra with our observations obtained in 2019 with ESO's newest high-resolution spectrograph ESPRESSO was especially revealing, from both an astronomical and an instrumentation point of view."

The old data indicated that the star in the Kinman Dwarf could have been undergoing a strong outburst period that likely ended sometime after 2011. Luminous blue variable stars such as this one are prone to experiencing giant outbursts over the course of their life, causing the stars' rate of mass loss to spike and their luminosity to increase dramatically.

Based on their observations and models, the astronomers have suggested two explanations for the star's disappearance and lack of a supernova, related to this possible outburst. The outburst may have resulted in the luminous blue variable being transformed into a less luminous star, which could also be partly hidden by dust. Alternatively, the team says the star may have collapsed into a black hole, without producing a supernova explosion. This would be a rare event: our current understanding of how massive stars die points to most of them ending their lives in a supernova.

Future studies are needed to confirm what fate befell this star. Planned to begin operations in 2025, ESO's Extremely Large Telescope (ELT) will be capable of resolving stars in distant galaxies such as the Kinman Dwarf, helping to solve cosmic mysteries such as this one.

New coatings on implants could help make them more compatible. Researchers at the Martin Luther University Halle-Wittenberg (MLU) have developed a new method of applying anti-inflammatory substances to implants in order to inhibit undesirable inflammatory reactions in the body. Their study was recently published in the International Journal of Molecular Sciences.

Implants, such as pacemakers or insulin pumps, are a regular part of modern medicine. However, it is not uncommon for complications to arise after implantation. The immune system identifies the implant as a foreign body and attempts to remove it. "This is actually a completely natural and useful reaction by the immune system," says Professor Thomas Groth, a biophysicist at MLU. It helps to heal wounds and kills harmful pathogens. If this reaction does not subside on its own after a few weeks, it can lead to chronic inflammation and more serious complications. "The immune system attracts various cells that try to isolate or remove the foreign entity. These include macrophages, a type of phagocyte, and other types of white blood cells and connective tissue cells," explains Groth. Implants can become encapsulated by connective tissue, which can be very painful for those affected. In addition, the implant is no longer able to function properly. Drugs that suppress the immune response in a systemic manner are often used to treat chronic inflammation, but may have undesired side effects.

Thomas Groth's team was looking for a simple way to modify the immune system's response to an implant in advance. "This is kind of tricky, because we obviously do not want to completely turn off the immune system as its processes are vital for healing wounds and killing pathogens. So, in fact we only wanted to modulate it," says the researcher. To do this, his team developed a new coating for implants that contains anti-inflammatory substances. For their new study, the team used two substances that are already known to have an anti-inflammatory effect: heparin and hyaluronic acid.

In the laboratory, the scientists treated a surface with the two substances by applying a layer that was only a few nanometres thick. "The layer is so thin that it does not affect how the implant functions. However, it must contain enough active substance to control the reaction of the immune system until the inflammatory reaction has subsided," adds Groth. In cell experiments, the researchers observed how the two substances were absorbed by the macrophages, thereby reducing inflammation in the cell cultures. The untreated cells showed clear signs of a pronounced inflammatory reaction. This is because the active substances inside the macrophages interfere with a specific signalling pathway that is crucial for the immune response and cell death. "Both heparin and hyaluronic acid prevent the release of certain pro-inflammatory messenger substances. Heparin is even more effective because it can be absorbed by macrophage cells," Groth concludes.

So far, the researchers have only tested the method on model surfaces and in cell cultures. Further studies on real implants and in model organisms are to follow.