Culture

An immunization strategy tested in mice protects against infection from SARS-CoV-2, as well as from potentially emerging animal coronaviruses, researchers say. The approach could be "used as described or easily adapted" to provide defense against newly discovered zoonotic coronaviruses. In the last 20 years, three betacoronaviruses have caused devastating disease in humans. The global pandemic caused by the latest such virus, SARS-CoV-2, highlights the need to protect against other strains that could present a threat to humans, possibly through a pan-coronavirus vaccine. To support related efforts, Alexander A. Cohen and colleagues used a "plug and display" approach to make a series of nanoparticles displaying the receptor-binding domain (RBD) of either SARS-CoV-2 alone ("homotypic nanoparticles") or the SARS-CoV-2 RBD along with a diverse set of RBDs from bat and pangolin betacoronaviruses that represent threats to humans ("mosaic nanoparticles"). In studies in mice, immunization with mosaic nanoparticles did not reduce immune response compared with immunization by a homotypic nanoparticle. What's more, mosaic nanoparticles generated cross-reactive immune responses in mice after one injection, whereas such responses required prime and boost injections in the case of the homotypic particle. The mosaic nanoparticles also elicited antibodies that, beyond recognizing the strains displayed, recognized mismatched strains, the authors say. Studying IgG antibodies from COVID-19 plasma donors, Cohen et al. found they exhibited little to no recognition of coronaviruses other than SARS-CoV-2, suggesting SARS-CoV-2-infection-induced immunity in humans would be unlikely to be protective against an outbreak of a new zoonotic coronavirus. This is yet another indication of the need to develop a vaccine to protect against emerging coronaviruses, they say. The results suggest mosaic nanoparticles as a candidate vaccine to protect against COVID-19 and other emerging coronaviruses with human spillover potential, write Cohen and team.

It's been more than a year since the first cases were identified in China, yet the exact origins of the COVID-19 pandemic remain a mystery. Though strong evidence suggests that the responsible coronavirus originated in bats, how and when it crossed from wildlife into humans is unknown.

In a study published online Jan.12 in the journal mBio, an international team of 15 biologists say this lack of clarity has exposed a glaring weakness in the current approach to pandemic surveillance and response worldwide.

In most recent studies of animal-borne pathogens with the potential to spread to humans, known as zoonotic pathogens, physical specimens of suspected wildlife hosts were not preserved. The practice of collecting and archiving specimens believed to harbor a virus, bacteria or parasite that's under investigation is called host vouchering.

"Vouchered specimens should be considered the gold standard in host-pathogen studies and a key part of pandemic preparedness," said Cody Thompson, co-lead author of the mBio paper and mammal collections manager at the University of Michigan Museum of Zoology.

"But host vouchering has effectively been nonexistent in most recent zoonotic pathogen studies, and the lack of this essential information has limited our ability to respond to the current COVID-19 pandemic," said Thompson, who is also an assistant research scientist in the U-M Department of Ecology and Evolutionary Biology.

To fill this knowledge gap, Thompson and his co-authors urge researchers who conduct host-pathogen studies to adopt vouchering practices and to collaborate with natural history museums to permanently archive host specimens, along with their tissue and microbiological samples.

The authors of the mBio article include experts in mammalogy, bat biology, microbiology, natural history, ornithology, bioinformatics, parasitology and host-pathogen biology. Most of them have ties to natural history museums.

"In essence, vouchering provides both an offensive mechanism for pandemic prevention--by expanding the surveillance of wildlife hosts and associated pathogens--and a defensive mechanism by providing a verifiable archive for baseline comparisons," said study co-lead author Kendra Phelps of EcoHealth Alliance, a global nonprofit that works to prevent pandemics and promote wildlife conservation.

"This problem becomes especially critical in navigating novel viral zoonoses, such as the COVID-19 pandemic, where it is necessary for the scientific community to swiftly and efficiently leverage its collective knowledge and resources to effectively understand and contain the spread of novel pathogens at a time when lockdown restrictions hamper on-going sampling efforts."

The emergence of infectious diseases attributed to novel pathogens that "spill over" from animal populations into humans has increased in recent decades.

The COVID-19 pandemic, in particular, has demonstrated that a previously unknown pathogen can emerge from wildlife species and threaten public health on a global scale within months. Experts from the World Health Organization are expected to arrive in China this week for a long-anticipated investigation into the pandemic's origins.

During spillover events, vouchered specimens in museum collections and biorepositories can help disease sleuths quickly track a pathogen to its source in the wild. The authors of the mBio study highlight three examples--yellow fever, hantaviruses and parasitic worms--of host-pathogen research that successfully incorporated natural history collections into collaborative research programs.

Vouchered host specimens can help answer fundamental biological, ecological and evolutionary questions about host-pathogen dynamics. The specimens allow for scientific replicability, they help ensure correct taxonomic identification of the host species, they establish a baseline for future studies, and they provide biological samples that can extend research as new technologies emerge.

At the same time, archiving host specimens in natural history collections provides access to a "vast, largely untapped biodiversity infrastructure" within museums, according to the authors of the mBio paper.

"We need to think of natural history collections as resources for preventing future pandemics, with the potential to promote powerful interdisciplinary and historical approaches to studying emerging zoonotic pathogens," said U-M's Thompson.

As part of their study, the mBio authors surveyed more than 100 microbiologists--bacteriologists, parasitologists and virologists--from around the world to assess their vouchering practices when conducting host-pathogen research.

Fewer than half said they voucher host specimens from which microbiological samples were lethally collected. In the cases where host specimens were obtained, most were deposited in the collections of natural history museums.

To help foster collaborations between microbiologists and curators of natural history collections, the authors also provide recommendations for integrating vouchering techniques and archiving of microbiological samples into host-pathogen studies.

Exercising regularly is one of the best defences against metabolic diseases, such as obesity and diabetes - but why? It's a question that scientists are still struggling to answer. While exercising changes the molecular behaviour of muscles, it's not well understood how these molecular changes improve metabolic health.

Scientists at the University of Copenhagen have now developed a new technology that allows researchers to study muscle biology on a more detailed level - and hopefully find some new answers. They extracted 'fast' and 'slow' twitch muscle fibers from freeze-dried muscle samples that were taken before and after 12 weeks of cycling exercise training. Their comprehensive analysis of the protein expression of the fibers provides new evidence that the fiber types respond differently to exercise training.

The research, which was published in Nature Communications, also demonstrates the untapped potential of freeze-dried samples that are located in freezers around the world.

"Metabolic disorders and several muscle diseases are known to affect or spare specific fiber types, therefore detailed investigation of specific fiber types is crucial. Previous studies involving large-scale protein analysis of muscle fibers required isolation of single muscle fibers from freshly obtained muscle biopsies. Since isolation of muscle fiber is time consuming, this approach has its inherent limitations. Our method enables muscle fiber analysis of already collected muscle biopsies as well as paves the new way for future studies," says Associate Professor Atul Deshmukh from the Novo Nordisk Foundation Center for Basic Metabolic Research (CBMR) at the University of Copenhagen.

Messy and confusing muscle samples

Skeletal muscle contains tiny fibers that can be categorised as either fast or slow twitch. Simply put, fast twitch fibers create explosive energy but get tired quickly, while slow twitch fibers are less energetic but have more endurance. Most people have an even number of both types in their muscles, but the ratio can vary widely between people. This means that exercise may benefit people differently, depending on this ratio.

In a muscle, thousands of fibers are bundled together by connective tissue and interspersed with a range of cell types with a supporting function. Because of all these different cell types, scientists can struggle to interpret the results of a whole muscle sample, and connect observed changes to specific cell types.

Understanding the potential of studying individual fibers, Atul Deshmukh teamed up with Professor Matthias Mann from the Novo Nordisk Foundation Center for Protein Research, and the Wojtaszewski Group from the Department of Nutrition, Exercise and Sports, both at the University of Copenhagen.

Honing in on muscle fibers

They recruited healthy individuals for 12 weeks of endurance exercise training and collected muscle samples before and after exercise, which were then freeze-dried. They then extracted fast and slow twitch muscle fibers from the samples and carried out high-resolution mass spectometry-based proteomics - a tool that allows scientists to measure thousands of proteins simultaneously in the different samples.

They identified more than 4,000 different proteins in the samples, and discovered that exercise training changed the expression of hundreds of different proteins in both fast and slow twitch fiber-types. Importantly, they discovered differences to the protein expression of the two fiber-types after exercise, which demonstrates that fast and slow twitch muscle respond differently.

"Our method can be scaled for high-throughput analysis of hundreds of individual muscle fibers from a single biopsy. Coupling this approach with the modern high sensitivity mass spectrometer may help to understand the fiber type heterogeneity in healthy and diseased skeletal muscle," says Associate Professor Atul Deshmukh from the Novo Nordisk Foundation Center for Basic Metabolic Research (CBMR) at the University of Copenhagen.

Drugs that don't accidentally target the heart

By mass, skeletal muscle is the largest organ in the body and even small changes can have tremendous impact on whole body metabolism. Skeletal muscle is therefore an interesting pharmacological target tissue with great potential in treatment of metabolic diseases. One challenge is however to avoid side effects in heart muscle, for example, which consists of specialized fibers with some similarities to slow twitch skeletal muscle fibers.

"Thus, our fiber-type specific protein repository is a first step toward identification of skeletal muscle proteins that are specific for fast twitch fibers, allowing drug targeting and delivery to this specific fiber type and potentially avoiding side effects in the heart," says Professor Jørgen Wojtaszewski from the Department of Nutrition, Exercise and Sports at the University of Copenhagen .

BOSTON -- By mid-November, the Centers for Disease Control and Prevention had reported that 218,439 health care workers in the U.S. had been infected with COVID-19 -- a likely underestimate due to incomplete data from states. About 3% to 4% of health care personnel who recover from coronavirus infection are expected to become "COVID long-haulers" as they cope with debilitating symptoms 12 to 18 months after the acute stage of the infection clears.

"As COVID-19 surges again, hospitals are facing a shortage of skilled frontline providers who can meet the relentless demands of caring for these patients," says Zeina N. Chemali, MD, MPH, a psychiatrist and neurologist at Massachusetts General Hospital (MGH) and senior author of an article in Lancet Respiratory Medicine on the challenges of health care workers who are COVID long-haulers. "Providers struggling with post-COVID complications will further strain the health care system unless medical institutions step up to support those who have sacrificed their health during the pandemic." Chemali directs MGH's McCance Center for Brain Health and the neuropsychiatry clinic, which treat COVID survivors with lingering symptoms.

Long-term complications of COVID can affect multiple organs in the body. Some people suffer neuropsychiatric complaints, such as overwhelming fatigue, brain fog, persistent headaches, altered sleep, anxiety, post-traumatic stress disorder and difficulty concentrating. They may also have cardiopulmonary symptoms -- fatigue after exertion, shortness of breath, persistent cough, heart arrhythmias, fluctuating blood pressure and fainting. Currently there are no curative treatments for post-COVID syndromes; therapy focuses on alleviating symptoms and coping strategies. Long-term complications of COVID can occur even in mild cases of the virus.

Chemali and her colleagues are calling for medical institutions to support and promote the safe return to work for all health care workers disabled from lingering symptoms of COVID. Current national return-to-work guidelines focus primarily on health care workers' infection status, leaving institutions to establish their own policies or for employees to opt for medical or disability leave. While some institutions have made accommodations for health care personnel as they return to work post-COVID, the measures may not apply to all affected workers, exacerbating existing social inequities. In addition, the culture of medicine elevates duty to patients over personal needs, leaving behind the wellness of its workforce.

The authors recommend that multidisciplinary teams at medical institutions be charged with devising back-to-work strategies for health care workers with long-term COVID symptoms. These strategies might include a gradual reintroduction into the work force, limiting shifts so natural circadian rhythms aren't disrupted, mandating frequent breaks and reducing workloads to prevent fatigue, and partnering with other providers to provide oversight during complex tasks and to share clinical responsibilities.

In addition, the authors are advocating for Congress to acknowledge the health issues and needs of long-hauler health care providers and for the new Biden administration to create funding to support health care workers as they recover from COVID. Previous U.S. government initiatives, such as the Coronavirus Aid, Relief, and Economic Security (CARES) Act, provided financial support to medical practices and hospitals struggling during the pandemic, but essential hospital workers disabled by the virus didn't individually benefit from the funding, says Chemali.

Medical institutions and society have a moral obligation to support health care veterans of the COVID war, says Chemali, who studies mental health and neurological disorders among refugees and in people living in war zones. "Whether frontline providers are taking care of people in war zones or in hospitals filled with patients with COVID, they are working in dangerous, very uncertain and stressful environments," says Chemali. "And yet they continue to perform their mission despite being overworked and burned out, which decreases their resilience and perhaps their immunity to the virus itself. We need to do better by health care workers who get sick with COVID. If we don't help survivors of COVID recover and return to work as providers, institutions risk losing even more of their skilled personnel, who will succumb to the exhaustion and stress caused by this relentless COVID tsunami."

A study of students at seven public universities across the United States has identified risk factors that may place students at higher risk for negative psychological impacts related to the COVID-19 pandemic. Factors associated with greater risk of negative impacts include the amount of time students spend on screens each day, their gender, age and other characteristics.

Research has shown many college students faced significant mental health challenges going into the COVID-19 pandemic, and experts say the pandemic has added new stressors. The findings, published in the journal PLOS ONE, could help experts tailor services to better support students. The observational study was drawn from a survey of more than 2,100 undergraduate and graduate students in the spring of 2020, when the students at all the universities included in the study had shifted to studying remotely.

"The pandemic is problematic for everyone, and we know that it's especially problematic for students who are eager to experience the unique social atmosphere that college life has to offer," said study co-author Lincoln Larson, associate professor of parks, recreation and tourism management at North Carolina State University. "COVID-19 has thrown a wrench into all of that. Our study found the pandemic is clearly taking a significant psychological toll on students."

In the survey, researchers asked students about the extent to which they felt negative emotions like fear, guilt, irritability, stress and worry when they thought about COVID-19. Researchers also asked open-ended question about how their feelings have changed since the start of the pandemic.

Students most commonly said in the open-ended responses that they felt unmotivated, anxious, stressed and isolated. More than 21 percent of students said they experienced feelings related to lack of motivation: some thought it was difficult to concentrate and others felt unproductive or that they were procrastinating. More than 17 percent said they felt anxious.

When the researchers analyzed students' responses to questions about the extent to which they felt specific emotions, they found 45 percent of students across the seven universities experienced a high risk of psychological impacts. Forty percent of students had a moderate psychological impact risk, and just 14 percent of students were in the low risk category.

The researchers used the data to identify characteristics linked to greater psychological impact from the pandemic. Female students, younger students aged 18 to 24 years, students who had more than eight hours per day of screen time and students who knew someone who contracted COVID-19 were more likely to experience negative psychological impacts from the pandemic, researchers found when they analyzed all of the factors that contributed to mental health risk.

"Our study documents that nearly half of college students were at a severe handicap in terms of their quality of life, education and social relationships because of their mental health during the early stages of the pandemic," said the study's lead author Matthew Browning, an assistant professor at Clemson University. "It also identifies the risk factors that can help colleges and universities target interventions or messaging to encourage these students to come and get help."

The researchers saw that in some cases, students' race or ethnicity and socio-economic status were linked to risk for high psychological impact when those factors were studied independently of others. Specifically, students who identified as Asian were at greater risk, as well as students with fair or poor health.

Spending two or more hours of daily time outdoors was linked to lower mental health impacts before adjusting for other risk factors. Researchers said those potential risk factors need further study.

Overall, they believe the findings could help universities tailor services for students.

"Campus leaders can devise creative interventions to facilitate social interactions and help students adopt more growth-oriented mindsets that turn this unique challenge into an opportunity," Larson said. "While some screen time may be necessary in this era of social distancing, there are still ways for students to connect, get outdoors and be active."

Across the nation, mental health experts have been working to address a growing prevalence of mental health issues among college and university students. A survey of college presidents in the fall of 2020 from the American Council on Education, in partnership with TIAA Institute, found the top two most pressing issues for presidents of four-year institutions were mental health of students and mental health of faculty and staff. On top of existing mental health challenges, the pandemic created new stressors, including increased isolation, said Monica Osburn, executive director of the North Carolina State University Counseling Center.

"Mental health was a significant challenge before COVID, and it absolutely exacerbated what students are feeling," Osburn said. "If you think about it from a developmental perspective, there are many developmental milestones that this group is experiencing loss around."

The NC State Counseling Center is offering virtual counseling appointments for students. For students who don't need counseling but are seeking support, NC State Prevention Services staff are also offering "drop-in" spaces for students to connect to talk about nature, racial and ethnic trauma, expression and the arts. There are also groups for students affected by loss of a loved one, and for coping with COVID-19. NC State Wellness and Recreation also offers online fitness classes and mind-body sessions for students.

"Any good data is helpful data because it gives us areas to target to be able to support students to make change," Osburn said of the study findings. "We want students to know it's OK to ask for help. We want them to reach out to get support. We want them to know: You don't have to go at it alone."

PHILADELPHIA -- (Jan. 12, 2021) -- Scientists at The Wistar Institute have created an advanced humanized immune system mouse model that allows them to examine resistance to immune checkpoint blockade therapies in melanoma. It has revealed a central role for mast cells. These findings were published today in the journal Nature Communications.

Checkpoint inhibitors revolutionized therapeutic options for advanced melanoma. However, only a fraction of patients respond to this treatment and some relapse due to reemergence of therapy-resistant lesions.

"To better understand why some cancers do not respond or become resistant to checkpoint therapies, we need more preclinical models that mimic the human tumor immune environment," said Rajasekharan Somasundaram, Ph.D., a member of The Wistar Institute Melanoma Research Center, who is the first and corresponding author of the paper.

Due to critical differences in the murine and human immune systems, mouse models do not allow the study of immune mechanisms that are uniquely human. "Humanized" mouse models are widely used to mimic the human immune system in mice.

Wistar's new humanized mouse model relies upon transplanted human stem cells and tissues that have been uniquely engineered to produce combinations of human cytokines that result in a more physiologically relevant model system for evaluating new immuno-oncology therapies and effective treatments targeting the tumor microenvironment.

"Our novel humanized mouse model has a longer life span and allowed us to study treatment responses to immunotherapies after human tumor transplant," said Somasundaram, who was part of a Wistar team led by Meenhard Herlyn, D.V.M., D.Sc., professor in The Wistar Institute Cancer Center, director of The Wistar Institute Melanoma Research Center, and a co-senior author on the study.

Researchers transplanted human metastatic melanoma cell lines into their humanized mouse model and treated them with anti-PD-1 antibody therapy. By studying immune cell infiltration into the tumors, Somasundaram and colleagues observed an abundance of infiltrated mast cells in anti-PD-1-treated tumors. Mast cells are an immune cell found throughout the body, especially in the skin and mucosa, where they serve as a first line of defense against pathogens. In samples from melanoma patients receiving immune checkpoint therapies, the team saw the same higher abundance of mast cells in non-responding tumors.

The authors showed that combining anti-PD-1 therapy with small molecule inhibitors able to deplete mast cells caused complete regression of tumors in mice and prolonged survival in comparison with mice receiving either treatment. Importantly, mice that reached remission did not show any signs of recurrence for four weeks after cessation of therapy and developed memory T cell response against melanoma tumors.

"Our results suggest that mast cells are associated with resistance to anti-PD-1 therapy, and that depleting mast cells is beneficial to immune checkpoint therapy responses," said Herlyn. "This warrants further investigation into the development of new combined immunotherapy approaches with small molecule inhibitors for the treatment of melanoma patients."

Gut microbes passed from female mice to their offspring, or shared between mice that live together, may influence the animals' bone mass, says a new study published today in eLife.

The findings suggest that treatments which alter the gut microbiome could help improve bone structure or treat conditions that weaken bones, such as osteoporosis.

"Genetics account for most of the variability in human bone density, but non-genetic factors such as gut microbes may also play a role," says lead author Abdul Malik Tyagi, Assistant Staff Scientist at the Division of Endocrinology, Metabolism, and Lipids at Emory Microbiome Research Center, Emory University, Georgia, US. "We wanted to investigate the influence of the microbiome on skeletal growth and bone mass development."

To do this, Tyagi and colleagues studied mice that lacked any gut microbes. They transferred fecal material containing a gut microbe called segmented filamentous bacteria (SFB), which stimulates the breakdown of bone, into the animals. Their studies revealed that the offspring of the SFB-treated mice were colonised with these bacteria at birth and had poorer bone structure than identical mice that lacked SFB.

Additionally, mice that lived with others carrying SFB became colonised with the bacteria within four weeks, and developed poorer bone structure as a result. "Our work shows that microbes can be either inherited or transmitted between individuals and significantly affects skeletal development in the animals," Tyagi says.

"Further studies are now needed to determine if the same is true in humans," adds senior author Roberto Pacifici, Garland Herndon Professor of Medicine, and Director of the Division of Endocrinology, Metabolism, and Lipids, at Emory University. "If it is, then it could be possible to develop therapies that change the gut microbiome early in life to allow for healthy skeletal growth.

"It would also suggest the need for caution in the current use of fecal transplants to treat other conditions in patients, to ensure that bone-weakening bacteria aren't inadvertently introduced," Pacifici concludes.

Using both mouse and human brain tissue, researchers at Yale School of Medicine have discovered that SARS-CoV-2 can directly infect the central nervous system and have begun to unravel some of the virus’s effects on brain cells. The study, published today in the Journal of Experimental Medicine (JEM), may help researchers develop treatments for the various neurological symptoms associated with COVID-19.

Though COVID-19 is considered to primarily be a respiratory disease, SARS-CoV-2 can affect many other organs in the body, including, in some patients, the central nervous system, where infection is associated with a variety of symptoms ranging from headaches and loss of taste and smell to impaired consciousness, delirium, strokes, and cerebral hemorrhage.

“Understanding the full extent of viral invasion is crucial to treating patients, as we begin to try to figure out the long-term consequences of COVID-19, many of which are predicted to involve the central nervous system,” says Akiko Iwasaki, a professor at Yale School of Medicine.

Many questions remain to be answered, including whether SARS-CoV-2 can infect neurons or other types of brain cells. To address this question, a team led by Iwasaki and co-senior author Kaya Bilguvar, an associate professor at Yale School of Medicine, analyzed the ability of SARS-CoV-2 to invade human brain organoids, miniature 3D organs grown in the lab from human stem cells. The researchers found that the virus was able to infect neurons in these organoids and use the neuronal cell machinery to replicate. The virus appears to facilitate its replication by boosting the metabolism of infected cells, while neighboring, uninfected neurons die as their oxygen supply is reduced.

SARS-CoV-2 enters lung cells by binding to a protein called ACE2, but whether this protein is present on the surface of brain cells is unclear. The Yale team determined that the ACE2 protein is, in fact, produced by neurons and that blocking this protein prevents the virus from human brain organoids.

SARS-CoV-2 was also able to infect the brains of mice genetically engineered to produce human ACE2, causing dramatic alterations in the brain’s blood vessels that could potentially disrupt the organ’s oxygen supply. Central nervous system infection was much more lethal in mice than infections limited to the lungs, the researchers found.

Finally, the researchers analyzed the brains of three patients who succumbed to COVID-19. SARS-CoV-2 was detected in the cortical neurons of one of these patients, and the infected brain regions were associated with ischemic infarcts in which decreased blood supply causes localized tissue damage and cell death. Microinfarcts were detected in the brain autopsy of all three patients.

“Our study clearly demonstrates that neurons can become a target of SARS-CoV-2 infection, with devastating consequences of localized ischemia in the brain and cell death,” Bilguvar says. “Our results suggest that neurologic symptoms associated with COVID-19 may be related to these consequences, and may help guide rational approaches to the treatment of COVID-19 patients with neuronal disorders.”

“Future studies will be needed to investigate what might predispose some patients to infections of the central nervous system and to determine the route of SARS-CoV-2 invasion into the brain and the sequence of infection in different cell types within the central nervous system that will help validate the temporal relationship between SARS-CoV-2 and ischemic infarcts in patients,” Iwasaki adds.

Almost 18,000 Americans experience traumatic spinal cord injuries every year. Many of these people are unable to use their hands and arms and can't do everyday tasks such as eating, grooming or drinking water without help.

Using physical therapy combined with a noninvasive method of stimulating nerve cells in the spinal cord, University of Washington researchers helped six Seattle area participants regain some hand and arm mobility. That increased mobility lasted at least three to six months after treatment had ended. The research team published these findings Jan. 5 in the journal IEEE Transactions on Neural Systems and Rehabilitation Engineering.

"We use our hands for everything -- eating, brushing our teeth, buttoning a shirt. Spinal cord injury patients rate regaining hand function as the absolute first priority for treatment. It is five to six times more important than anything else that they ask for help on," said lead author Dr. Fatma Inanici, a UW senior postdoctoral researcher in electrical and computer engineering who completed this research as a doctoral student of rehabilitation medicine in the UW School of Medicine.

"At the beginning of our study," Inanici said, "I didn't expect such an immediate response starting from the very first stimulation session. As a rehabilitation physician, my experience was that there was always a limit to how much people would recover. But now it looks like that's changing. It's so rewarding to see these results."

After a spinal cord injury, many patients do physical therapy to help them attempt to regain mobility. Recently, a series of studies have shown that implanting a stimulator to deliver electric current to a damaged spinal cord could help paralyzed patients walk again.

The UW team, composed of researchers from the Center for Neurotechnology, combined stimulation with standard physical therapy exercises, but the stimulation doesn't require surgery. Instead, it involves small patches that stick to a participant's skin like a Band-Aid. These patches are placed around the injured area on the back of the neck where they deliver electrical pulses.

The researchers recruited six people with chronic spinal cord injuries. All participants had been injured for at least a year and a half. Some participants couldn't wiggle their fingers or thumbs while others had some mobility at the beginning of the study.

To explore the viability of using the skin-surface stimulation method, the researchers designed a five-month training program. For the first month, the researchers monitored participants' baseline limb movements each week. Then for the second month, the team put participants through intensive physical therapy training, three times a week for two hours at a time. For the third month, participants continued physical therapy training but with stimulation added.

"We turned on the device, but they continued doing the exact same exercises they did the previous month, progressing to slightly more difficult versions if they improved," Inanici said.

For the last two months of the study, participants were divided into two categories: Participants with less severe injuries received another month of training alone and then a month of training plus stimulation. Patients with more severe injuries received the opposite -- training and stimulation first, followed by only training second.

While some participants regained some hand function during training alone, all six saw improvements when stimulation was combined with training.

"Both people who had no hand movement at the beginning of the study started moving their hands again during stimulation, and were able to produce a measurable force between their fingers and thumb," said senior author Chet Moritz, a UW associate professor of electrical and computer engineering, rehabilitation medicine and physiology and biophysics. "That's a dramatic change, to go from being completely paralyzed below the wrists down to moving your hands at will."

In addition, some participants noticed other improvements, including a more normal heart rate and better regulation of body temperature and bladder function.

The team followed up with participants for up to six months after training and found that these improvements remained, despite no more stimulation.

"We think these stimulators bring the nerves that make your muscles contract very close to being active. They don't actually cause the muscle to move, but they get it ready to move. It's primed, like the sprinter at the start of a race," said Moritz, who is also the co-director of the Center for Neurotechnology. "Then when someone with a spinal cord injury wants to move, the few connections that might have been spared around the injury are enough to cause those muscles to contract."

The research is moving toward helping people in the clinic. The results of this study have already informed the design of an international multi-site clinical trial that will be co-led by Moritz. One of the lead sites will be at the UW.

"We're seeing a common theme across universities -- stimulating the spinal cord electrically is making people better," Moritz said. "But it does take motivation. The stimulator helps you do the exercises, and the exercises help you get stronger, but the improvements are incremental. Over time, however, they add up into something that's really astounding."

A recent study finds that, in the wake of a mass shooting, National Rifle Association (NRA) employees, donors and volunteers had extremely mixed emotions about the organization - reporting higher levels of both positive and negative feelings about the NRA, as compared to people with no NRA affiliation.

"We wanted to see what effect 'in-group' affiliation and political identity had on how people responded to the NRA's actions after a mass shooting," says Yang Cheng, co-author of the study and an assistant professor of communication at North Carolina State University. "The political findings were predictable - Republicans thought more favorably of the NRA than Democrats did. But the in-group affiliation was a lot more complex than we anticipated.

"The people most critical of the NRA were the people most closely affiliated with it - but those were also the people most hopeful about the organization."

For this study, the researchers conducted an online survey of 603 U.S. adults. Given the nature of the study, it's important to understand the make-up of the study participants. Approximately 63% of the participants, or 378 people, were neither affiliated with the NRA nor supportive of it. The study also include 56 NRA employees, which made up 9% of the participants; 51 NRA members (8.5%); three NRA donors (0.5%); seven NRA volunteers (1.2%); and 108 people (17.9%) who were not NRA members, but who supported the organization. In terms of political affiliation, there were 274 Democrats (45.4%); 199 Republicans (33%); and 130 people who did not identify as Republicans or Democrats (21.6%). The survey was conducted in the wake of the 2018 shooting at Marjory Stoneman Douglas High School in Parkland, Florida.

The survey questions were designed to capture how study participants felt about the NRA's response to the Parkland shooting.

Broadly speaking, the findings were consistent with what one would expect. For example, people who said they support the NRA had more positive feelings about the NRA's actions than people who said they did not support the NRA. But there were some surprises.

For example, it's not surprising that NRA employees and donors reported having the most positive feelings towards the NRA's actions, such as hope. NRA volunteers were a close second.

But it is surprising that NRA employees, donors and volunteers also reported the highest negative emotions toward the NRA's actions after the Parkland shooting. Negative emotions, in this context, include fear, anger and disgust.

NRA donors and employees also reported the highest levels of "conflict judgment," meaning they felt the most strongly that the organization was not handling the crisis well. Examples of relevant questions from the survey include: "I don't like much of what the NRA did after the shooting" and "The NRA's actions after this shooting were harmful to me personally."

"Our findings suggest that in-group members, while supportive of the organization, are even more critical than out-group members," Cheng says. "That was not what we were anticipating, based on traditional social identity research."

On the other hand, Cheng notes that political partisanship did make a difference, with Democrats and Republicans taking clearly delineated stances toward the NRA.

"The finding raises some questions about how non-profit organizations need to think about crisis communications, at least in the context of gun control issues," Cheng says. "It also highlights the need for more issue-specific research, since there can clearly be significant deviations from what you would anticipate if you were looking only at the available literature."

WASHINGTON -- Researchers have developed a new laser-based process for 3D printing intricate parts made of glass. With further development, the new method could be useful for making complex optics for vision, imaging, illumination or laser-based applications.

"Most 3D printing processes build up an object layer by layer," said research team leader Laurent Gallais from The Fresnel Institute and Ecole Centrale Marseille in France. "Our new process avoids the limitations of these processes by using a laser beam to transform -- or polymerize -- a liquid precursor into solid glass."

In The Optical Society (OSA) journal Optics Letters, Gallais and research team members Thomas Doualle and Jean-Claude Andre demonstrate how they used the new technique to create detailed objects in a 3D volume without using the classical layer-by-layer approach. Using this approach, they created a variety of silica glass objects such as miniature models of a bike and the Eiffel Tower without any pores or cracks.

The 3D printing approach is based on multiphoton polymerization, which ensures that polymerization, a process that links liquid monomer molecules together into a solid polymer, only takes place at the precise laser focal point. It allows direct fabrication of 3D parts that range in size from a few microns to tens of centimeters with a resolution that is theoretically only limited by the optics used for laser beam shaping.

"Glass is one of the primary materials used to make optics," said Gallais. "Our work represents a first step toward developing a process that could one day allow scientists to 3D print the optical components they need."

Finding the right material

Using a traditional layer-by-layer approach to build 3D glass objects comes with several limitations. The speed of the printing process is limited by the time it takes to build the layers, and it can be difficult to create layers with consistent thicknesses when using highly viscous resins. Making complex parts typically requires supports, which must be precisely positioned and then removed once the object hardens.

Although multiphoton polymerization can be used to avoid the layer-by-layer approach, 3D printing glass objects requires a material that is transparent at the wavelength of the laser both during the initial liquid phase and once polymerized. It must also absorb the laser light at half the laser wavelength to initiate the multiphoton polymerization process.

To accomplish this, the researchers used a mixture containing a photochemical initiator to absorb the laser light, a resin and high concentration of silica nanoparticles. In addition to working well with the laser, this mixture's high viscosity allows a 3D part to be formed without deformation problems or supports to keep the object in place during 3D printing.

"Critical to the technique were high power ultrashort lasers based on Strickland and Mourou's chirped pulse amplification technology recognized with a Nobel prize in 2018," said Gallais. "Only intense and very short pulses will create non-linear photo polymerization with high precision and no thermal effects."

Testing the process

After validating that a solid object could be created using the silica nanoparticle mixtures, the researchers used their 3D printing approach to create objects with complex shapes. They also applied a process that transforms the polymerized parts into glass.

"Our approach could potentially be used to produce almost any type of 3D glass object," said Gallais. "For example, we are exploring the possibility of producing glass parts that could be used on luxury watches or perfume bottles."

The researchers are working to make the technique more practical and reduce cost by experimenting with less expensive laser sources, for example. They also want to optimize the process to improve the surface quality to decrease roughness.

One-third of the fertilizer applied to grow corn in the U.S. each year simply compensates for the ongoing loss of soil fertility, leading to more than a half-billion dollars in extra costs to U.S. farmers every year, finds new research from the University of Colorado Boulder published last month in Earth's Future.

Long-term soil fertility is on the decline in agricultural lands around the world due to salinization, acidification, erosion and the loss of important nutrients in the soil such as nitrogen and phosphorus. Corn farmers in the U.S. offset these losses with nitrogen and phosphorus fertilizers also intended to boost yields, but scientists have never calculated how much of this fertilizer goes into just regaining baseline soil fertility--or how much that costs.

"We know there's land degradation going on even in U.S. modern agriculture, but it's really difficult to pin down how much and what impact it has," said Jason Neff, corresponding author on the paper and director of the Sustainability Innovation Lab at Colorado (SILC). "These findings provide more information to farmers so they can make decisions that benefit them economically, but also support a more sustainable form of high-yield agriculture."

The U.S. is one of the most productive countries in the world when it comes to corn, growing more than 4.46 tons per acre farmed. In the 2018-19 growing season alone, U.S. farms produced more than 366 million metric tons of corn which generated $14.5 billion in revenue. The U.S. is also one of the world's largest users of fertilizer, applying more nitrogen and phosphorus per acre than its high-yield agricultural counterparts in the European Union.

But using fertilizer doesn't just cost farmers and governments money. It also comes at an environmental cost. A large portion of the global greenhouse gas emissions caused by agriculture--24% of global emissions in 2010 and 10% of U.S. emissions in 2018--comes from fertilizer production. This means that steps taken to reduce fertilizer use also help address rising greenhouse gases.

Excess nitrogen and phosphorus that runs off fields and into rivers and lakes also creates unhealthy conditions for freshwater and marine life, and is responsible for the Dead Zone in the Gulf of Mexico--a large area depleted of oxygen and devoid of ocean life, including many commercially important species. When we consider not only dollars spent by farmers but also nutrient loss and impacts to the Mississippi River, the costs go from billions to over a trillion dollars every year, said Neff.

"If you can drop the fertilization, while maintaining the yields that we need and the economic outcomes that farmers want, then why not, right? That's a win-win," said Neff.

Untangling the true cost of fertilizer

To separate out this true cost of fertilizer from other modern agricultural inputs, Neff and his colleagues ran a series of scenario-based model analyses using the Environmental Policy Integrated Climate (EPIC) model, a widely used agronomic model used to estimate crop growth and how crop growth responds to variables like fertilizer, irrigation and climate.

"Doing that lets us then untangle, what's going on with degradation," he said. "What's going on when you change a system from natural to agricultural, and how much of an impact does that have on the nutrients available for plant growth?"

The researchers used four scenarios in this model to compare how using no fertilizer or irrigation--as is in done in many developing economies--differed from using only one or the other, or both (which is common practice in the U.S.). Irrigation was an important component of the analyses because while it can increase yields, it also increases erosion and fertilizer runoff.

By separating the impacts of fertilizer and irrigation, the researchers could see in different regions of the U.S. where each was more important than the other for agricultural success. In California, farmers add more water. In Ohio, fertilizer additions are more important than irrigation. But across the country, they found that it took a whopping one third of fertilizer presently added to cornfields to simply break even, bringing soil fertility back to pre-farmed levels.

Farming smarter

While this may sound like bad news, Neff sees it as a golden opportunity: with more information, farmers can make better decisions.

"Farmers do what makes sense to grow crops. When you're not able to see the cumulative effects of degradation, you have to add fertilizers but you're not going to know what the financial impact of that underlying degradation is," said Neff.

Practices like regenerative agriculture, which restore soil fertility on lands actively being farmed, will also reduce the costs and environmental impacts of fertilizer use. Healthier, more fertile soils can also capture more carbon, hold more water and keep excess nutrients from running off into ecosystems that can't handle them.

Farmers can reduce how often they till their fields, add and increase erosion control measures, as well as use more organic fertilizers, like compost. These can actually help reduce the amount of inorganic fertilizers--nitrogen and phosphorus--needed in the soil.

"My hope is that this information supports national and international efforts to build back soil fertility," said Neff.

Every field has its underlying principles. For economics it's the rational actor; biology has the theory of evolution; modern geology rests on the bedrock of plate tectonics.

Physics has conservation laws and symmetries. For instance, the law of conservation of energy - which holds that energy can neither be created nor destroyed -- has guided research in physics since antiquity, becoming more formalized as time went on. Likewise, parity symmetry suggests that switching an event for its mirror image shouldn't affect the outcome.

As physicists have worked to understand the truly bizarre rules of quantum mechanics, it seems that some of these symmetries don't always hold up. Professor Andrew Jayich focuses on investigating these symmetry violations in an effort to shed light on new physics. He and his lab members have just published a paper in Physical Review Letters reporting progress on synthesizing and detecting ions that are among the most sensitive measures for time (T) symmetry violations.

Time symmetry implies that the laws of physics look the same when time runs forward or backward. "For example, the path of a pool ball on a table simply retraces its course if the arrow of time is reversed," Jayich said. But that does not hold for all physical interactions.

Understanding when and why T symmetry breaks down could provide answers to some of the biggest open questions in physics, such as why the Universe is full of matter and lacks antimatter. "The laws of physics as we know them treat matter and antimatter on equal footing," Jayich said, "yet events in the early moments of the Universe favored matter over antimatter." These are tough problems to crack, with close to a century of work behind them.

To address these questions, Jayich and his team have controllably synthesized, trapped and cooled radioactive molecules, RaOCH3+ and RaOH+, that provide large improvements in sensitivity to T symmetry violation. First author Mingyu Fan, a doctoral student in Jayich's lab, discovered a technique to detect dark ions in their electromagnetic trap. These particles don't scatter light, which means the researchers can't detect them with a camera.

While adjusting some of the experimental parameters, Fan noticed the trapped ions, which normally sit very still, were oscillating rapidly at a large yet fixed amplitude. He figured out that this behavior provides a strong signal for detecting these elusive ions. "This controlled amplification of the motion allows us to measure the ion's motional frequency, and thus its mass precisely and quickly," Fan said.

Jayich and Fan reported their success in laser cooling radium ions in a previous study, which was the first to achieve this feat for the heavy element. The lab's recent breakthrough brings them closer to their ultimate goal of using radioactive molecules to test time symmetry violations.

The researchers used radium-226, which has 138 neutrons and no nuclear spin, in their recent work. They plan to use the slightly lighter isotope, radium-225, which has the necessary nuclear spin, in their planned symmetry violation experiments. Other members of the lab are working on efforts to laser cool and trap radium-225 ions and perform optical spectroscopy on the radioactive molecules that contain it.

"These results are a clear breakthrough for our planned 'big' experiments," said Jayich. "We have made these incredibly sensitive detectors, where a single molecule has the sensitivity to set new limits on T-violation. This opens up a new paradigm for measuring T-violation."

Most flowering plants depend on pollinators such as bees to transfer pollen from the male anthers of one flower to the female stigma of another flower, enabling fertilization and the production of fruits and seeds. Bee pollination, however, involves an inherent conflict of interest, because bees are only interested in pollen as a food source.

"The bee and the plant have different goals, so plants have evolved ways to optimize the behavior of bees to maximize the transfer of pollen between flowers," explained Kathleen Kay, associate professor of ecology and evolutionary biology at UC Santa Cruz.

In a study published December 23 in Proceedings of the Royal Society B, Kay's team described a pollination strategy involving flowers with two distinct sets of anthers that differ in color, size, and position. Darwin was mystified by such flowers, lamenting in a letter that he had "wasted enormous effort over them, and cannot yet get a glimpse of the meaning of the parts."

For years, the only explanation put forth for this phenomenon, called heteranthery, was that one set of anthers is specialized for attracting and feeding bees, while a less conspicuous set of anthers surreptitiously dusts them with pollen for transfer to another flower. This "division of labor" hypothesis has been tested in various species, and although it does seem to apply in a few cases, many studies have failed to confirm it.

The new study proposes a different explanation and shows how it works in species of wildflowers in the genus Clarkia. Through a variety of greenhouse and field experiments, Kay's team showed that heteranthery in Clarkia is a way for flowers to gradually present their pollen to bees over multiple visits.

"What's happening is the anthers open at different times, so the plant is doling out pollen to the bees gradually," Kay said.

This "pollen dosing" strategy is a way of getting the bees to move on to another flower without stopping to groom the pollen off their bodies and pack it away for delivery to their nest. Bees are highly specialized for pollen feeding, with hairs on their bodies that attract pollen electrostatically, stiff hairs on their legs for grooming, and structures for storing pollen on their legs or bodies.

"If a flower doses a bee with a ton of pollen, the bee is in pollen heaven and it will start grooming and then go off to feed its offspring without visiting another flower," Kay said. "So plants have different mechanisms for doling out pollen gradually. In this case, the flower is hiding some anthers and gradually revealing them to pollinators, and that limits how much pollen a bee can remove in each visit."

There are about 41 species of Clarkia in California, and about half of them have two types of anthers. These tend to be pollinated by specialized species of native solitary bees. Kay's team focused on bee pollination in two species of Clarkia, C. unguiculata (elegant clarkia) and C. cylindrica (speckled clarkia).

In these and other heterantherous clarkias, an inner whorl of anthers stands erect in the center of the flower, is visually conspicuous, and matures early, releasing its pollen first. An inconspicuous outer whorl lies back against the petals until after the inner anthers have opened. The outer anthers then move toward the center of the flower and begin to release their pollen gradually. A few days later, the stigma becomes erect and sticky, ready to receive pollen from another flower.

"In the field, you can see flowers in different stages, and using time-lapse photography we could see the whole sequence of events in individual flowers," Kay said.

The division of labor hypothesis requires both sets of anthers to be producing pollen at the same time. Kay said she decided to investigate heteranthery after observing clarkia flowers at a field site and realizing that explanation didn't fit. "I could see some flowers where one set was active, and some where the other set was active, but no flowers where both were active at the same time," she said.

In C. cylindrica, the two sets of anthers produce pollen with different colors, which enabled the researchers to track where it was going. Their experiments showed that pollen from both sets of anthers was collected for food and was also being transferred between flowers, contradicting the division of labor hypothesis.

"The color difference was convenient, because otherwise it's very hard to track pollen," Kay said. "We showed that bees are collecting and transporting pollen from both kinds of anthers, so they are not specialized for different functions."

Kay said she didn't realize how much time Darwin had spent puzzling over heteranthery until she started studying it herself. "He figured out so many things, it's hard to find a case where he didn't figure it out," she said. Darwin might have been on the right track, though. Shortly before his death, he requested seeds of C. unguiculata to use in experiments.

In addition to Kay, the coauthors of the paper include postdoctoral scholar Tania Jogesh and two UCSC undergraduates, Diana Tataru and Sami Akiba. Both students completed senior theses on their work and were supported by UCSC's Norris Center for Natural History.

COLUMBUS, Ohio - For those trying to live a healthy lifestyle, the choice between sugar and artificial sweeteners such as saccharin can be confusing. A new study led by researchers at The Ohio State University Wexner Medical Center and The Ohio State University College of Medicine found the sugar substitute saccharin doesn't lead to the development of diabetes in healthy adults as previous studies have suggested.

The study findings are published in the journal Microbiome.

"It's not that the findings of previous studies are wrong, they just didn't adequately control for things like underlying health conditions, diet choices and lifestyle habits," said George Kyriazis, assistant professor of biological chemistry and pharmacology at Ohio State and senior author of the study. "By studying the artificial sweetener saccharin in healthy adults, we've isolated its effects and found no change in participants' gut microbiome or their metabolic profiles, as it was previously suggested."

Kyriazis collaborated with researchers at Ohio State's College of Food, Agricultural & Environmental Sciences, Ohio State's College of Arts and Sciences, Sanford Burnham Prebys Medical Discovery Institute in California and the Translational Research Institute for Metabolism and Diabetes at Advent-Health in Florida.

Non-caloric artificial sweeteners are often consumed as a substitute for dietary sugars, and saccharin is one of six artificial sweeteners approved by the Food and Drug Administration.

The use of artificial sweeteners has increased dramatically over the past decade due to growing awareness of the negative health outcomes associated with consuming too much sugar, study authors noted.

"Previous studies elsewhere have suggested that consuming artificial sweeteners is associated with metabolic syndrome, weight gain, obesity and non-alcoholic fatty liver disease. These findings have raised concerns that consuming them may lead to adverse public health outcomes, and a lack of well-controlled interventional studies contributed to the confusion," said study first author Joan Serrano, a researcher in the department of biological chemistry and pharmacology at Ohio State.

A total of 46 healthy adults ages 18-45 with body mass indexes of 25 or less completed this randomized, double-blind, placebo-controlled study.

Participants ingested capsules that contained the maximum acceptable daily amount of either saccharin, or lactisole (a sweet taste receptor inhibitor, or saccharin with lactisole or placebo every day for two weeks. The maximum acceptable daily amount of saccharin is 400 milligrams per day, which is far more than the average consumer would consume.

The study excluded people with acute or chronic medical conditions or taking medications that could potentially affect metabolic function, such as diabetes, bariatric surgery, inflammatory bowel disease or a history of malabsorption and pregnant or nursing.

Researchers also tested for 10 weeks the effects of even higher dose of saccharin in mice that genetically lack sweet taste receptors with the same results: the artificial sweetener didn't affect glucose tolerance, or cause any significant gut microbiota changes or apparent adverse health effects.

"Sugar, on the other hand, is well-documented to contribute to obesity, heart disease and diabetes," Kyriazis said. "So when given the choice, artificial sweeteners such as saccharin are the clear winner based on all of the scientific information we currently have."

Future research will study each FDA-approved sweetener individually to examine if there are any differences in how they're metabolized. Researchers will study these substances over a longer period of time to ensure they're safe for daily use.