Culture

When a patient is diagnosed with rheumatoid arthritis, psoriatic arthritis or spondyloarthritis, prescribing the correct type of medicine is a case of trial and error. It is simply not possible to predict which medication will work for the individual patient, and it is therefore a matter of trying the different treatment options: glucocorticoids, low dose chemotherapeutic drugs or newer biological drugs. Until now!

A new research project from Aarhus University and Aarhus University Hospital in Denmark suggest that it is the composition of cells in the joint of the individual patient which determines whether the medicine is effective or not. The researcher behind the study, published in the journal of the American College of Rheumatology (ACR Open), is medical doctor and PhD Tue Wenzel Kragstrup from the Department of Biomedicine at Aarhus University and the Department of Rheumatology at Aarhus University Hospital.

"So far, we've examined the effect of nine drugs in three different in vitro models. We can see that the effect of a given drug depends on the cell compositions. This leads us to hope that the immunological cells and inflammatory signalling molecules in the joint of each individual patient will be able to predict the most effective treatment," says Tue Wenzel Kragstrup.

The study's in vitro models consist of cell cultures isolated from joint fluids aspirated from the joints of patients with severe arthritis as part of the treatment at Aarhus University Hospital. The researchers then used the diseased cells from the joint fluid to examine the effects of different types of medicine, explains Tue Wenzel Kragstrup's colleague, Ph.D. student Morten Aagaard Nielsen from the Department og Biomedicine, who is first author of the article.

"As far as we know, this is the first description of a direct association between the composition of the immune system cells and the effect of medication," Morten Aagaard Nielsen says. Tue Wenzel Kragstrup adds:

"The findings are based on the assumption that the cells in the test tube behaving like they would behave in the patient. So of course, the research result must be validated in humans in a larger number of patients," says Tue Wenzel Kragstrup, who concurrent with his biomedical research is in rheumatology specialist training.

It was at the hospital while meeting patients racked with pain, that Tue Wenzel Kragstrup got the idea and invented the project.

"Today, the first-choice drug has no effect in around one in three patients. So, doctors often have to try several different types of medicine before they find the right one. This is a process that may take years, because a drug typically takes three to four months to be effective," explains Tue Wenzel Kragstrup.

"And while we wait, the patients continue to experience swelling and pain - not to mention the permanent damage that can occur in the joints as a result of persistent inflammation," he says.

Tue Wenzel Kragstrup hopes that the research results in time can be translated into a simple test - such as a blood test - which can determine the correct medicine for the individual patient. According to Tue Wenzel Kragstrup, this type of individualised treatment could be realised within a decade.

Rheumatoid arthritis, psoriatic arthritis and lumbar arthritis - more information:

Rheumatoid arthritis, psoriatic arthritis and spondyloarthritis affects approx. two per cent of Denmark's population, often young people, with no known cure.

The diseases can be very painful and disabling and may therefore have a major impact on families and working life.

Rheumatoid arthritis, psoriatic arthritis and spondyloarthritis are characterised by an over-reaction in the immune system with inflammation of the affected joints.

ANN ARBOR--Conventional thinking is that bone regeneration is left to a small number of mighty cells called skeletal stem cells, which reside within larger groups of bone marrow stromal cells.

But new findings from the University of Michigan recasts that thinking.

In a recent study, Noriaki Ono, assistant professor at the U-M School of Dentistry, and colleagues report that mature bone marrow stromal cells metamorphosed to perform in ways similar to their bone-healing stem cell cousins--but only after an injury.

Bone fracture is an emergency for humans and all vertebrates, so the sooner cells start the business of healing damaged bone--and the more cells there are to do it--the better.

"Our study shows that other cells besides skeletal stem cells can do this job as well," Ono said.

In the mouse study, inert Cxcl12 cells in bone marrow responded to post-injury cellular cues by converting into regenerative cells, much like skeletal stem cells. Normally, the main job of these Cxcl12-expressing cells, widely known as CAR cells, is to secrete cytokines, which help regulate neighboring blood cells. They were recruited for healing only after an injury.

"The surprise in our study is that these cells essentially did nothing in terms of making bones, when bones grow longer," Ono said. "It's only when bones are injured that these cells start rushing to repair the defect."

This is important because the remarkable regenerative potential of bones is generally attributed to rare skeletal stem cells, Ono says. These new findings raise the possibility that these mighty skeletal stem cells could be generated through the transformation of the more available mature stromal cells.

These mature stromal cells are malleable and readily available throughout life, and could potentially provide an excellent cellular source for bone and tissue regeneration, Ono says.

CHAMPAIGN, Ill. -- Before they can get started at their field site - a giant cave studded with stalactites, stalagmites and human artifacts - 15 undergraduate students must figure out how to use their virtual hands and tools. They also must learn to teleport. (VIDEO)

This is ANTH 399, a course designed to bring the archaeological field school experience to undergraduate students who never leave campus. Designed by University of Illinois professors and computer science graduate students, the course satisfies the field school requirement for those pursuing an archaeology degree at Illinois.

"Field school is a requirement of most archaeological programs across the country," said Illinois anthropology professor Laura Shackelford, who led development of the class with U. of I. education policy, organization and leadership professor Wenhao David Huang and computer science graduate student Cameron Merrill. "But traveling to a field school site can cost anywhere from $500 to $5,000."

This, and the fact that traditional field school expeditions are often scheduled during breaks, makes it difficult or impossible for many students to attend - cutting them off from the study of archaeology altogether.

"This class makes it possible for many more students to get an education or explore a career in archaeology," Shackelford said. The class is also accessible to students with physical limitations who are unable to travel to or navigate a field site.

The virtual cave is modeled in part on a real cave that was excavated in the 1930s. It contains both ancient and more recent human artifacts, all of which are accessible to students who dig in the right place.

The students learn the archaeological techniques required in any excavation. They set up a research grid on the cave floor and systematically locate and record any artifacts they find on the surface. They draw a map with all of the surface details and then decide where to excavate. They take photos of special features or finds. They dig. They collect artifacts. They conduct laboratory analyses. They keep track of their progress in a field notebook.

All of these tasks are accomplished in the virtual world.

Building this virtual archaeological experience is a computational and creative challenge, said computer science graduate student Merrill, the lead programmer on the project. This class is his doctoral thesis.

"You can't just import lectures into VR and expect to have good results," Merrill said. "We're not creating a 3D model viewer for looking at artifacts or to tour an existing site. We're trying to build an immersive educational experience."

Students need to feel they are actually engaged in excavating a cave, he said. It's also important for them to use realistic tools to accomplish the tasks at hand.

But designing virtual tools for an archaeological dig is tricky, Merrill said.

"A lot of the challenge has to do with the trade-off between making something as realistic as possible versus making something more accessible to people," he said. For example, the designers created a virtual tape measure that requires two hands to operate. But reading tiny measurements in the virtual world is problematic, so a pop-up screen shows the user the readout on the tape.

Virtual digging was another challenge.

"We needed to simulate dirt that the students can modify in real time," Merrill said. "But simulating something like soil is very computationally complex."

The team came up with a solution that allows students to extract the dirt in chunks that reflect the light in a realistic manner. The design also incorporates haptic feedback, so that students can "feel" the solidity and texture of the dirt when they make contact.

The team uses insights from game design to engage the students, Shackelford said.

"We're giving them less instruction and providing multiple scenarios," she said. "And so it's possible different teams of students will experience different things."

The students choose where to dig, which influences the information they gather - or miss, Shackelford said. And there are risks, too. Dig too far into a wall and it might collapse.

In the first iteration of the class held last year, students gave the designers immediate feedback about how the tools worked or didn't work, allowing Merrill and his colleagues to tweak them. He and his colleagues have created more than 110 artifacts, many of which are virtual versions of actual relics in the university's collections.

"When we want them to learn how to do some ceramic analysis and sorting, we'll bring the real things to class and they'll be going back and forth between the real and virtual worlds," Shackelford said.

The students work in pairs, taking turns in the virtual world while their partner guides them, following their progress on a computer monitor and stopping them from bumping into any real-world objects. The excavations lead to laboratory work, which also occurs in the virtual realm, Shackelford said.

"There's a lab on faunal analysis, there's a lab on pollen analysis," she said. "They're doing ceramic sorting and identification. They're doing seriation, which is putting things in the correct chronological order."

They also learn stratigraphy, the art of reading how layers of soil were deposited over time.

"The pattern and the timing of that deposition of soil tells us a lot about how a site was formed, Shackelford said.

The team is evaluating the efficacy of the program to determine if the skills the students learn are equivalent to those obtained in a real-world dig. In the earlier version of the class, professors took the students to a real-world "mock excavation" site near campus at the end of the semester. This site allowed the students to excavate in real dirt, testing their VR-acquired skills and understanding.

"We found that a lot of things that were frustrating for students in the virtual reality world were just as frustrating in the real world," Shackelford said. "And with a little practice and self-correction, they were able to do everything that we asked them to."

Joint press release by Charité and the DZIF

First identified in 2012, the MERS-coronavirus is capable of causing severe and often fatal pneumonia. There are no effective treatments for MERS. Researchers from the German Center for Infection Research (DZIF) at Charité - Universitätsmedizin Berlin recently identified a cellular recycling process known as autophagy as a potential target in the fight against MERS. Autophagy-inducing substances - including certain licensed drugs - were shown to be capable of drastically reducing the rate at which the virus replicates. Results from this research have been published in Nature Communications*.

The MERS pathogen is capable of causing a flu-like illness (Middle East Respiratory Syndrome) which is often associated with pneumonia. Since its appearance in 2012, approximately 2,500 cases have been reported to the WHO across a total of 27 countries. Approximately one third of infections have resulted in death. A team co-led by PD Dr. Marcel Müller of the Institute of Virology on Campus Charité Mitte recently discovered that the MERS virus can only replicate efficiently if it inhibits a cellular process known as autophagy. Based on this initial discovery, the researchers went on to identify substances which are capable of inducing autophagy and can thus be used to limit viral infection.

The term autophagy refers to a type of cellular recycling process which enables cells to dispose of damaged materials and waste products, while retaining intact components for incorporation into new cellular structures. This autophagic degradation, or 'auto-digestion', is also capable of identifying pathogen-derived components, such as the building blocks of viruses, which are treated as waste products and eliminated. A range of viruses are known to have developed strategies to dysregulate or inhibit autophagy. PD Dr. Müller and his colleagues therefore set out to determine whether the MERS virus is capable of modulating autophagic degradation. As a first step, and using stringent biosafety conditions, the researchers infected cells with the MERS virus. Subsequent observations revealed a disruption to the cellular recycling process in cells infected with the virus. "This result clearly indicated that the MERS pathogen benefits from an attenuation of the cellular recycling process," explains PD Dr. Müller.

The researchers also succeeded in identifying a previously unknown molecular switch which regulates the process of autophagic degradation: the SKP2 protein. The researchers discovered that the MERS virus activates this molecular switch in order to slow down the cell's recycling processes and avoid degradation. Using these new insights, the researchers treated MERS-infected cells with various SKP2 inhibitors in order to stimulate the degradation process. This strategy proved successful, the autophagy-inhibiting substances reducing viral replication by a factor of 28,000. Among the substances used to elicit this effect were licensed drugs such as niclosamide, a treatment for tapeworms which had previously been identified as an SKP2 inhibitor. Importantly, niclosamide was shown to be capable of drastically reducing the replication of the MERS virus in cell culture.

"Our results reveal SKP2 to be a promising starting point for the development of new substances capable of fighting the MERS virus, and potentially even other autophagy-dependent viruses," says PD Dr. Müller. SKP2 inhibitors do not target the virus directly. For this reason, the research group leader expects their use to be associated with a reduced risk of resistance. "However, SKP2 inhibitors will need to be tested in vivo before they can be used as drugs. Furthermore, one has to properly evaluate the risks and benefits for their in vivo use, since even drugs that have already been approved can have side effects," says the virologist. The researchers will also test whether SKP2 inhibitors could be effective against other coronaviruses such as SARS or the novel coronavirus (2019-nCoV) which is currently emerging in China.

Writing in the journal Stem Cells Translational Medicine, an international research team, led by physician-scientists at University of California San Diego School of Medicine, describe a new method for delivering neural precursor cells (NSCs) to spinal cord injuries in rats, reducing the risk of further injury and boosting the propagation of potentially reparative cells.

The findings are published in the Jan. 29, 2020 print issue.

NSCs hold great potential for treating a variety of neurodegenerative diseases and injuries to the spinal cord. The stem cells possess the ability to differentiate into multiple types of neural cell, depending upon their environment. As a result, there is great interest and much effort to use these cells to repair spinal cord injuries and effectively restore related functions.

But current spinal cell delivery techniques, said Martin Marsala, MD, professor in the Department of Anesthesiology at UC San Diego School of Medicine, involve direct needle injection into the spinal parenchyma -- the primary cord of nerve fibers running through the vertebral column. "As such, there is an inherent risk of (further) spinal tissue injury or intraparechymal bleeding," said Marsala.

The new technique is less invasive, depositing injected cells into the spinal subpial space -- a space between the pial membrane and the superficial layers of the spinal cord.

"This injection technique allows the delivery of high cell numbers from a single injection," said Marsala. "Cells with proliferative properties, such as glial progenitors, then migrate into the spinal parenchyma and populate over time in multiple spinal segments as well as the brain stem. Injected cells acquire the functional properties consistent with surrounding host cells."

Marsala, senior author Joseph Ciacci, MD, a neurosurgeon at UC San Diego Health, and colleagues suggest that subpially-injected cells are likely to accelerate and improve treatment potency in cell-replacement therapies for several spinal neurodegenerative disorders in which a broad repopulation by glial cells, such as oligodendrocytes or astrocytes, is desired.

"This may include spinal traumatic injury, amyotrophic lateral sclerosis and multiple sclerosis," said Ciacci.

The researchers plan to test the cell delivery system in larger preclinical animal models of spinal traumatic injury that more closely mimic human anatomy and size. "The goal is to define the optimal cell dosing and timing of cell delivery after spinal injury, which is associated with the best treatment effect," said Marsala.

Autism is characterized in part by an individual's challenges communicating and interacting socially with others. These difficulties have typically been studied in isolation by focusing on cognitive and behavioral differences in those with autism spectrum disorder, but little work has been done on how exchanges for autistic people unfold in the real world.

Researchers at The University of Texas at Dallas recently turned the spotlight on social interaction in autism by examining it as a two-way street. Their results, published in December in the journal Autism, suggest that successful interactions for autistic adults revolve around partner compatibility and not just the skill set of either person.

"Most studies attempting to understand social disability in autism focus exclusively on individual characteristics," said Dr. Noah Sasson, an associate professor in the School of Behavioral and Brain Sciences (BBS) and corresponding author of the study. "This presumes that any difficulties in social interaction are driven solely by the autistic person. But how each person influences and is influenced by the other is key to understanding affiliation and social quality."

The study focused on the so-called "double-empathy problem," which predicts that two people who are neurologically different and have distinct modes of communication and understanding may have trouble connecting with each other, as commonly occurs in interactions between autistic and non-autistic adults.

"It's not just that autistic adults can struggle to infer the thoughts and motivations of typically developing adults, which has been well documented; the reverse is true as well. Non-autistic people struggle to infer what autistic people are thinking," Sasson said. "Anecdotally, many autistic people often report better quality of social interaction when engaging with other autistic people. We set out to test this empirically."

Kerrianne Morrison MS'16, PhD'19, the paper's lead author, explained that the concept of a social-interaction difficulty being a two-sided, relational problem -- and not simply a shortcoming of the autistic person -- is only beginning to take hold.

"Autism is such a young field of study. Examining differences depending on the context of social situations rather than dysfunction across all contexts is starting to gain traction in academia," she said. "We believe this represents a better understanding of how people with autism can thrive in the right contexts."

In the study, 125 adults held a five-minute, unstructured "getting-to-know-you" conversation with an unfamiliar person. Sixty-seven of the participants had been diagnosed with autism. Each participant then independently evaluated the quality of the interaction and their first impressions of their partner.

Autistic adults were not rated as less intelligent, trustworthy or likable by either the autistic or typically developing cohort, and importantly, autistic participants' interactions with other autistic adults were viewed by them as more favorable than those with typically developing partners.

"While typically developing participants preferred future interaction with other typically developing partners over autistic partners," Sasson said, "autistic adults actually trended toward the opposite, preferring future interaction with other autistic adults. They also disclosed more about themselves to autistic partners and felt closer to their partners than did typically developing participants."

Autistic adults were rated as more awkward and less socially warm than typically developing adults by both autistic and typically developing partners. Some judgments were more favorable than those from Sasson's previous studies in which people evaluated autistic adults in videos.

"Direct interaction seems to lessen some negative evaluations of autism," Sasson said. "This aligns with previous work suggesting that direct experience and knowledge of autism can reduce stigma and promote inclusion."

Typically developing participants also rated the conversational content with autistic and typically developing partners to be of similar quality. This shows that negative evaluations of autistic adults by non-autistic adults may be based more on social presentation differences and not their actual conversations.

"These findings suggest that social interaction difficulties in autism are not an absolute characteristic of the individual," Sasson said. "Rather, social quality is a relational characteristic that depends upon the fit between the person and the social environment. If autistic people were inherently poor at social interaction, you'd expect an interaction between two autistic people to be even more of a struggle than between an autistic and non-autistic person. But that's not what we found."

Sasson said that he hopes this work shows that studying actual social interaction elicits a deeper understanding than studying individual abilities alone.

"Social disability in autism is context-dependent and emerges more in interactions with typically developing partners," he said. "This likely reflects a mismatch in cognitive and communication styles that may improve with increased familiarity and acceptance."

Morrison believes that this research is illuminating a crucial portion of the story for the autistic community.

"We're moving beyond the existing research, which has fixated on social abilities in isolated, standardized contexts, and addressing this blind spot of real-world outcomes," she said. "Particularly in adults, this is the information we need."

DURHAM, N.C. -- Biomedical engineers at Duke University have demonstrated that at least 25 percent of antibiotic-resistant pathogenic bacteria found in clinical settings are capable of spreading their resistance directly to other bacteria. At the same time, the study shows that, despite common beliefs, the use of antibiotics does not significantly affect the rate at which the genes responsible for resistance are swapped between bacteria.

Researchers used a new high-throughput method of measuring the rate at which bacteria exchange the packages of DNA that bestow resistance. The speed and ability to automate much of the process could allow new insights into what variables affect transfer rates. Such efforts could help doctors slow--or even reverse--the spread of resistance in certain human pathogens.

The results appears online on January 24 in the journal Science Advances.

"Our previous research showed that antibiotics do not affect the rate at which bacteria spread their resistance directly to their community in laboratory strains of E.coli," said Lingchong You, professor of biomedical engineering at Duke. "But we wanted to see if this is also true for clinical strains of pathogens that are actually out there in the world."

Each antibiotic-resistant pathogen carries a genetic recipe for its resistance. But like chocolate chip cookies, not all recipes are the same, and not all of them are easily taught to others. One way of transferring resistance, however, is for that genetic recipe to be neatly written into a sharable book of sorts called a plasmid, which is then picked up and read by a neighboring bacteria through a process called conjugation.

As resistance to antibiotics grows around the world, scientists are trying to figure out how to stop it from spreading. But because a lot of antibiotics come from natural sources, it would be impossible to completely eliminate resistance in the wild, which means there will always be reservoirs of bacteria filled with recipe books for resistance.

"So the real problem is the resistance making its way into pathogens that harm humans," said Jonathan Bethke, a PhD student working in You's laboratory and first author of the new paper. "We're looking to gain a good understanding of what factors affect their rate of conjugation, because if you can slow that process down enough, the plasmids carrying the genes for resistance can fall out of a population."

One major challenge in accomplishing that, however, is the classical method of measuring the rate of plasmid conjugation. Besides being labor intensive, researchers must wait 16 hours for a new generation of bacteria to grow in Petri dishes before they can get the results. This restriction makes this approach difficult to use when dealing with hundreds of bacterial strains and dozens of tweakable variables.

Rather than taking years to finish the experiment, Bethke and Allison Lopatkin, a former graduate student in You's laboratory who is now an assistant professor at Barnard College, developed a method that uses automated machinery and takes only five hours to deliver results. It involves mixing two strains of bacteria -- a donor strain with resistance to one antibiotic that can be shared through plasmid conjugation and a recipient strain with resistance to a different antibiotic that cannot be shared.

After letting the strains mingle and the plasmid conjugation process take place for a set amount of time, the bacterial mixture is transferred to vials containing nutrients and both antibiotics. This promotes the growth of the recipient bacteria that have successfully received the donor's plasmids for resistance while stunting the growth of all the rest. The researchers then wait to see how long the newly dual-resistant population takes to hit a certain threshold, which indicates how many there were to begin with.

"This method opens up the ability to test many more drugs or environmental factors to see how they influence the rate of plasmid conjugation," said Bethke. "It will also allow us to determine if there's some sort of genetic determinant that is playing a greater role in terms of the transfer rate."

You and Bethke collaborated with Joshua Thaden, assistant professor of medicine at Duke, and Vance Fowler, professor of medicine at Duke, to obtain 219 clinical isolates of pathogens - bugs found in real patients. All carried resistance to beta-lactamase, the most common form of antibiotic in use today. By measuring the rate of plasmid conjugation both with and without beta-lactamase antibiotics present, they showed that, except for one outlier, these antibiotics do not increase the rate of sharing resistance. They also discovered that more than 25 percent of the strains studied are capable of sharing their resistance at rates fast enough to detect.

"We were surprised to discover that it was that high," said You. "And of course antibiotics do promote the spread of resistance, but our study indicates that it is primarily through selective population dynamics rather than through an increased rate of plasmid conjugation."

The researchers also examined how slight variations in the genetics of the resistance plasmids themselves affect their conjugation rate. Working with Minfeng Xiao's laboratory at BGI Genomics in Shenzhen, China, the team sequenced the plasmids and analyzed their DNA. They then categorized the plasmids into "mobility groups" based on how they jump between cells and "incompatibility groups" based on how they replicate. Much to the researchers' surprise, they discovered that while there were only two mobility groups present in their sample library, neither of which affected the rate of conjugation, there were seven incompatibility groups -- and they very much did affect the rate of conjugation.

"This is a preliminary but potentially big discovery because these two classifications are genetic, which makes them easy to identify," said Bethke. "If we can start to build a library of genetic markers that indicate what a pathogen's ability to spread its resistance directly to its neighbors is likely to be, then we can start to make large predictions about things like horizontal gene transfer networks and maybe start understanding how bacteria are evolving through this process at large."

"Such a library would also have direct implications for how doctors use antibiotics in the field," said You. "This knowledge would help doctors make patient-specific decisions on whether or not to administer antibiotics."

MADISON, Wis. -- University of Wisconsin-Madison researchers have developed nanoparticles that, in the lab, can activate immune responses to cancer cells. If they are shown to work as well in the body as they do in the lab, the nanoparticles might provide an effective and more affordable way to fight cancer.

They are cheaper to produce and easier to engineer than the antibodies that underlie current immunotherapies, which as drugs cost tens of thousands of dollars a month.

"Immunotherapy basically boosts the patient's own immune system to fight against cancer cells better," says Seungpyo Hong, a professor in the UW-Madison School of Pharmacy. "The antibodies that are used right now are large, they're expensive, they're hard to engineer, and they don't always show the highest level of efficacy either. So we wanted to explore other ways to activate the immune system."

Hong and postdoctoral associate Woo-jin Jeong led the study, published online Jan. 2 in the Journal of the American Chemical Society, with collaborators at the University of Illinois at Chicago. It's the first demonstration that nanoparticles can act as immunotherapy agents.

More research is needed to understand their effectiveness in the body, but Hong has applied for a patent on the new nanoparticles and is now testing them in animal models.

In tests against lab-grown strains of cancer, the nanoparticles boosted production of the immune stimulating protein interleukin-2 by T cells, one kind of immune cell in the body, by about 50 percent compared to no treatment. They were just as effective as antibodies. The nanoparticles were also able to improve the effectiveness of the chemotherapy drug doxorubicin in similar tests.

Normally, T cells produce a protein named PD-1 that acts like an off switch for immune responses. This "checkpoint" helps keep T cells from improperly attacking healthy cells.

Some cancer cells hide from the immune system by tricking checkpoints on T cells. They imitate healthy cells by producing proteins called PD-L1, which bind to the off switch and let tumors hide in plain sight. Several immunotherapies use antibodies -- proteins that bind other proteins -- against either PD-1 or PD-L1 to disrupt this connection.

"The key here is if you block that binding very efficiently, you can now reactivate the T cells, so the T cells start attacking the tumor cells," says Hong.

But a course of those antibodies, known as checkpoint inhibitors, can cost upwards of $100,000 because pure antibodies are difficult and expensive to produce. Like these antibodies, the nanoparticles the researchers developed gum up the PD-L1 on cancer cells so they can't activate the off switch on T cells. Hong's lab used a different approach to achieve the same effect.

They took small chunks, or peptides, of the PD-1 protein and attached them to branched nanoparticles. The nanoparticles stabilize these peptides so they're able to bind to PD-L1 on the cancer cells much like the full PD-1 protein can. They also have a lot of branches, so they can hold many copies of the PD-1 peptides and bind more strongly to PD-L1.

In test tubes, the nanoparticles attached to PD-L1 as strongly as full-sized antibodies did. A strong connection between the nanoparticles and PD-L1 means the cancer cells can no longer use these proteins to trick T cells.

Both the peptides and the nanoparticles they're attached to are simple and cheap to produce in the lab. And both can easily be tinkered with and altered, so future research might be able to optimize them to work better by following this early proof-of-concept study.

"The bottom line is that, for the first time, we developed this peptide-nanoparticle platform for immunotherapy and found clear evidence that this system has great potential," says Hong. "We're looking forward to the next step."

What makes people more or less mindful from one situation to the next? Researchers have found that mindfulness is not entirely something an individual brings to a situation and rather is partly shaped by the situations they encounter.

"As mindfulness has become prevalent within organizational practice and scholarly research on organizations, there is a growing need to situate mindfulness more fully within organizational contexts," said Christopher S. Reina, Ph.D., assistant professor in the Virginia Commonwealth University Department of Management and Entrepreneurship in the School of Business.

In "Wherever you go, there you become: How mindfulness arises in everyday situations," published in the journal Organizational Behavior and Human Decision Processes, Reina and co-author Ravi S. Kudesia, Ph.D., assistant professor at the Temple University Fox School of Business, introduce a theoretical framework that explains how mindfulness arises based on an individual's capacity for self-regulation as well as three motivational forces: their metacognitive beliefs, their mental fatigue and how they appraise the situations they experience.

While metacognitive beliefs aid individuals in higher levels of self-regulation, mental fatigue draws resources away from self-regulation. Meanwhile, how individuals appraise a situation influence how much self-regulation is needed to maintain mindfulness.

"These motivational aspects of mindfulness have received little attention to date," Reina said. "Despite the increasing prevalence of mindfulness in organizational research, we have yet to seriously consider its antecedents: how and why people become more or less mindful from one situation to the next." In other words, while researchers have previously explored what mindfulness predicts, little to no research has studied what predicts mindfulness, which represents the core contribution of Reina's study.

The research comprises over 558 participants and 9,390 responses from across three separate studies.

If mindfulness indeed produces positive outcomes, it seems important to identify what situational features can increase or decrease mindfulness. Understanding this can help managers better design organizational situations that enhance mindfulness, Reina said.

"Mindfulness is often assumed to be something that people bring with them into situations, some stable psychological property that is inherent to them," the study concludes. "The present research helps nuance this assumption. If we instead see mindfulness as arising from the coming together of people and their situations, we can better conceptualize mindfulness and design organizational situations that enhance it."

The brain undergoes dramatic change during the first years of life. Its circuits readily rewire as an infant and then child encounters new sights and sounds, taking in the world and learning to understand it. As the child matures and key developmental periods pass, the brain becomes less malleable--but certain experiences create opportunities for parts of the adult brain to rewire and learn again.

New research by Billy Lau, a postdoctoral researcher working with Assistant Professor Keerthi Krishnan in the Department of Biochemistry and Cellular and Molecular Biology in the University of Tennessee, Knoxville's College of Arts and Sciences, examines the time during which an adult female mouse first learns to recognize and respond to the distress cries of young mouse pups as one such opportunity for rewiring.

The findings were published earlier this month in the Journal of Neuroscience and hint at potential therapeutic strategies for Rett syndrome, a rare neurodevelopmental disorder.

Krishnan's lab researches how mutated genes affect brain plasticity, ultimately leading to neurological diseases, specifically Rett syndrome. In humans, mutations in the gene MECP2 cause Rett syndrome. Children with Rett syndrome appear to develop normally for the first several months of life but later begin to lose language and motor skills.

"Children diagnosed with neurodevelopmental disorders eventually grow up and continue to exhibit symptoms throughout life," Krishnan said. "Though much research is focused on identifying and diagnosing neurodevelopmental disorders, much work needs to be done to help improve or manage symptoms for patients throughout their life. Rett syndrome mainly affects girls and women worldwide; very few studies focus on pathology of the disorder in adult women."

For several years, Lau and Krishnan have been conducting research with a team at Cold Spring Harbor Laboratory headed by Stephen Shea and Josh Huang. In their previous work, the team discovered that female mice lacking one functional copy of Mecp2 failed to respond to the distress cries of their young. The scientists honed in on the abnormal behavior of a group of neurons in the auditory cortex called parvalbumin (PV) neurons together with higher protein expression of perineuronal nets (PNNs), structures that improve connections within the brain.

"PVs and PNNs are thought to be inhibitory, acting as a brake in the brain that prevents learning," Lau said. "In the new study, we tested this hypothesis. Our findings reveal a physiological mechanism underlying the progression of Rett syndrome that may extend to other brain regions."

In the new study, Lau and the other members of the team took a closer look at how exposure to the young pups changes signaling within the auditory cortex of female mice. By monitoring the activity of individual cells in this part of the brain, the researchers found that when Mecp2 is intact, the dampening effect of PNNs and PV neurons decreases following exposure to the pups. This allows other neurons in the circuit to become more responsive to the young animals' cries. This change occurred even in mice that had never been pregnant. In female mice whose Mecp2 gene was impaired, however, the dampening signals remained strong.

The findings support previous evidence that the function of PV neurons is particularly vulnerable to the loss of Mecp2, suggesting that these cells or the circuits they are involved in may be appropriate targets for drug development and that patients with Rett syndrome may be most responsive to treatment during certain periods of life in conjunction with their environment and social experience.

"This work has implications in continuing to understand what roles Mecp2 plays in typical brain activity and function, especially in complex social situations, similar to what patients encounter in their daily lives," Krishnan said. "If we understand the mechanisms and roles of this protein in social communication and perception, we will be able to find ways to compensate for lack of this protein through therapeutic or rehabilitative treatments."

DALLAS - Jan. 29, 2020 - In a new report published today in Circulation, experts outline national and global goals to help people live healthier for longer. While heart disease and stroke-related deaths continue to decline, the rate at which they're declining has slowed and obesity rates are on the rise.

"We believe every person should enjoy health and well-being no matter their age, gender, race, or even the zip code in which they live. And we know disparities exist even to that level -- from one block of a city to another," says John Warner, M.D., Executive Vice President for Health System Affairs at UT Southwestern Medical Center and senior author on the report. The American Heart Association 2030 Impact Goals aim to help all people live healthier for more years of their life:

Across the U.S.: Together, we will equitably increase healthy life expectancy from 66 to 68 years by 2030.

Around the world: Together with global and local collaborators, we will equitably increase worldwide healthy life expectancy from 64 to at least 67 years by 2030.

According to the report, the trend toward cardiovascular health around the U.S. has been generally positive, with adults getting more active and people eating healthier, smoking less, and better controlling their cholesterol. However, some areas continue to worsen: Nearly 40 percent of adults and 18.5 percent of youth in the U.S. are now obese; only 26 percent of U.S. youth meet the national recommendations of an hour a day of moderate to vigorous activity; and between 1990 and 2017 diabetes prevalence in the U.S. increased 129.7 percent for men and 120.9 percent for women.

"To improve individual health, we must make the environments where we live, work, learn, and play equitably supportive of healthy behaviors. We also need to help people better understand the impact their communities have in driving choices for health and well-being," Warner says.

2019-nCoV likely emerged very recently and was detected relatively rapidly.

The virus may use the same molecular 'doorway' as severe acute respiratory syndrome (SARS) to enter human cells.

A new genetic analysis of 10 genome sequences of novel coronavirus (2019-nCoV) from nine patients in Wuhan finds that the virus is most closely related to two bat-derived SARS-like coronaviruses, according to a study published in The Lancet.

The authors say that although their analysis suggests that bats might be the original host of the virus, an animal sold at the Huanan seafood market in Wuhan might represent an intermediate host that enables the emergence of the virus in humans. For this reason, the future evolution, adaptation and spread of this virus requires urgent investigation.

In the study, the authors report the epidemiological data of nine patients who were diagnosed with viral pneumonia of unidentified cause. Cell and secretion samples were taken from the patients' lungs to harvest samples of the 2019-nCoV virus, which were analysed to determine the origin of the virus and how it enters human cells.

Eight of the patients had visited the Huanan seafood market. One patient had never visited the market, but had stayed in a hotel near the market before the onset of their illness.

The authors found 2019-nCoV in all 10 genetic samples taken from the patients - including eight complete genomes, and two partial genomes. The genetic sequences of the samples were nearly identical (shared more than 99.98% of the same genetic sequence) - which indicates a very recent emergence of the virus into humans.

"It is striking that the sequences of 2019-nCoV described here from different patients were almost identical. This finding suggests that 2019-nCoV originated from one source within a very short period and was detected relatively rapidly. However, as the virus transmits to more individuals, constant surveillance of mutations arising is needed," says one of lead authors Professor Weifeng Shi, Key Laboratory of Etiology and Epidemiology of Emerging Infectious Diseases in Universities of Shandong, Shandong First Medical University and Shandong Academy of Medical Sciences, China. [1]

Comparing the 2019-nCoV genetic sequence with a library of viruses, the authors found that the most closely related viruses were two SARS-like coronaviruses of bat origin - bat-SL-CoVZC45 and bat-SL-CoVZXC21 - which shared 88% of the genetic sequence. 2019-nCoV was more genetically distant to the human SARS virus (which shared about 79% of the genetic sequence) and the Middle East respiratory syndrome (MERS) virus (which shared about 50% of the genetic sequence).

Studying the spike protein of the virus (how it binds then enters human cells), the authors found that 2019-nCoV and human SARS virus have similar structures, despite some small differences. As a result, the authors suggest that 2019-nCoV might use the same molecular doorway to enter the cells as SARS (a receptor called ACE2), but note that this will require confirmation.

Based on their data, the authors say that it seems likely that the 2019-nCoV causing the Wuhan outbreak might also be initially hosted by bats and transmitted to humans via a currently unknown wild animal sold at the Huanan seafood market.

They say that it is more likely that bat coronaviruses are mutating, than 2019-nCoV - meaning that 2019-nCoV is unlikely to have emerged due to a chance mutation. However, more information is needed, and if a more closely related animal virus is identified, this suggestion could be wrong.

"These data are consistent with a bat reservoir for coronaviruses in general and 2019-nCoV in particular. However, despite the importance of bats, it seems likely that another animal host is acting as an intermediate host between bats and humans," says Professor Guizhen Wu, Chinese Center for Disease Control and Prevention.

Explaining this she notes: "First, the outbreak was first reported in late December, 2019, when most bat species in Wuhan are hibernating. Second, no bats were sold or found at the Huanan seafood market, whereas many non-aquatic animals (including mammals) were. Third, the similarities in the genetic sequences between 2019-nCoV and its close relatives bat-SL-CoVZC45 and bat-SL-CoVZXC21 were less than 90%, meaningthese two bat-derived coronaviruses are not direct ancestors of 2019-nCoV. Fourth, in both SARS and MERS, bats acted as the natural reservoir, with another animal acting as an intermediate host, and with humans as terminal hosts.This again highlights the hidden virus reservoir in wild animals and their potential to spill over into human populations." [1]

Highly active adults engage in a greater variety of physical activities than do less active adults, finds a new study led by researchers at NYU Rory Meyers College of Nursing.

The study, published in the journal Translational Behavioral Medicine, also revealed that walking is the most common type of exercise, followed by cycling and dancing.

Physical activity is a cornerstone of a healthy lifestyle and has been shown to reduce the risk of many illnesses, including cardiovascular disease, diabetes, certain cancers, and depression. National guidelines recommend that adults get 150 minutes of moderate-intensity exercise, 75 minutes of vigorous exercise, or a combination of the two each week. However, more than half of U.S. adults do not meet these recommendations.

Physical activity guidelines do not account for the type or variety of activities--for instance, whether someone meets the recommendation by jogging for half an hour five days a week, taking two vigorous boot camp classes, or doing a combination of walking, swimming, and cycling.

"Developing a better understanding of patterns of physical activity, and the individual factors related to these patterns, could inform targeted interventions to increase physical activity," said Susan Malone, PhD, RN, an assistant professor at NYU Rory Meyers College of Nursing and the study's lead author.

Malone and her colleagues analyzed patterns of physical activity across multiple dimensions (frequency, duration, and type of exercise) among a national sample of 9,816 U.S. adults using the CDC's National Health and Nutrition Examination Survey (2003-2006). They also examined demographic and health characteristics and how these factors were linked to different patterns of physical activity.

Notably, the researchers found that highly active adults participate in a greater number of activities, with active adults engaging in at least two different activity types in the last month and the most active participating in five.

"Since a greater variety of activities was associated with meeting exercise guidelines, mixing up your workouts to vary the type of exercise could be beneficial," said Malone.

Walking is the most common type of physical activity, with more than 30 percent of all adults walking an average of four times a week for roughly 40 minutes at a time. After walking, cycling and dancing are the most popular activities.

Among adults who exercise, the researchers identified five "clusters" of physical activity patterns: low frequency, short duration (13 percent of exercising adults); low frequency, long duration (7 percent); daily frequency, short duration (55 percent); daily frequency, long duration (7 percent); and high frequency, average duration (18 percent).

High-activity clusters (daily frequency, long duration and high frequency, average duration) had a greater proportion of younger, white, non-smoking men with at least a high school education. In contrast, active women were more likely to engage in short but frequent bouts of activity.

"There are several scheduling and social barriers that could explain why this pattern of shorter, frequent activity may be more attainable for women as compared to men. For instance, research shows that women have less leisure time, reporting an average of 13.2 hours of household labor per week compared to 6.6 hours for men," said Malone.

Finally, the researchers found that 44 percent of adults report no physical activity; adults with chronic conditions and poor health behaviors like smoking are more likely to fall into this group that does not exercise. Nonetheless, a small percentage of adults with chronic conditions do exercise regularly, suggesting that they can incorporate physical activity into their lifestyles.

"When encouraging their patients to exercise, clinicians should not just ask about frequency, but also what types of physical activities their patients do. They may even suggest engaging in a variety of activities," said Malone. "The ultimate goal is to develop targeted interventions to help people stick to their exercise plans and lower their disease risk."

Members of disadvantaged social groups who engage in contact with members of privileged groups are less likely to support social change toward equality, a multinational study by social psychologists at the University of Zurich shows. To reduce this effect, it is important to actively address and acknowledge inequalities in intergroup contacts.

Are members of advantaged groups, such as white Americans who interact with those of disadvantaged groups such as black compatriots, more likely to support their rights and concerns? And what happens to the commitment among the disadvantaged group members? For more than 50 years, social researchers, and policy-makers have believed that having members of different groups interact with each other can be an effective tool for reducing prejudice and building mutual trust. However, new research findings suggest that positive contact between groups might mask existing group disparities and, therefore, perpetuate rather than challenge structural inequalities.

Survey responses from 13,000 individuals across 69 countries

Tabea Hässler and Johannes Ullrich from the Department of Psychology of the University of Zurich have carried out a statistical investigation into whether and how contact between groups might help to promote support for social change, in pursuit of greater social equality. Working together with a multinational team of 43 researchers, they gathered survey responses from almost 13,000 individuals across 69 countries. The survey respondents included people from advantaged social groups (ethnic or religious majorities and heterosexual people) and members of minority groups, who are socially disadvantaged as a result of their ethnic or religious background, sexual orientation or gender identity.

Different effects on support for social change

The research findings suggest that when members of historically advantaged groups interact with disadvantaged groups, they are more likely to support social change toward equality. For example, heterosexual individuals who experience positive contact with homosexual, bisexual or transgender individuals at work or in their private lives are more likely to take part in demonstrations, sign petitions, discuss inequalities or vote in favor of nondiscrimination rules.

But for members of historically disadvantaged groups, the research team observed the reverse trend: If they had friends or acquaintances in the privileged group, they were generally less likely to support social change to promote equality. "In other words, if an immigrant has frequent positive interactions with people from the host society, then this person might be less aware of the obstacles that immigrants still face," explains first author Tabea Hässler. "They are also less committed to eliminating these inequalities."

Both groups willing to work in solidarity

However, the researchers also point out an important exception. Among members of both advantaged and disadvantaged groups, contact between groups predicted a greater willingness to work in solidarity to achieve greater social equality - for example, to attend a demonstration together. "This willingness to work together in solidarity unites people from all groups and may offer a new route to reach social cohesion and social change," concludes Johannes Ullrich, professor at UZH. In addition, the researchers suggest that advantaged group members who engage in contact should openly acknowledge structural inequalities and express support for efforts by disadvantaged group members to reduce these inequalities. The researchers believe that this could possibly prevent intergroup contact from leading to reduced engagement of disadvantaged group members. "After all, social harmony should not come at the expense of social justice," says Ullrich.

A Dartmouth-led study finds that two common economic interventions in Afghanistan designed to improve economic livelihoods and win the "hearts of minds" of civilians was ineffective in reducing support for the Taliban in the long run.

When civilians support the insurgency, they are more apt to provide assistance to combatants, such as by providing food or tips on the government's whereabouts, or even by joining the insurgent effort. The study is the first to examine how cash transfers and vocational training administered by a humanitarian organization affect combatant support in an active conflict zone. The findings are published in the February 2020 issue of American Political Science Review.

Working with Mercy Corps, the Dartmouth-led research team assessed how vulnerable youth's political attitudes towards the Afghan government and Taliban was affected by two economic interventions: job training and cash. The program, Introducing New Vocational Education and Skills Training (INVEST), was designed to help lift at-risk youth (age 20+) in Kandahar, Afghanistan, out of poverty and minimize the likelihood that they would join the insurgency.

Approximately 2,600 Afghan men and women (average age of 20), took part in the study. Nearly 80 percent had shared Pashtun ethnicity with the Taliban, and just over half of them had experienced forced displacement in the past by either the NATO-led International Security Assistance Force or Taliban.

Participants were randomly assigned to one of four economic interventions, where they received either job training, cash, job training and cash, or no aid at all. The job training was comprised of either three or six months of coursework at one of the local vocational training centers in Kandahar, as well as other skills building. As for the cash, a one-time, unconditional cash transfer of US $75 was wired to a recipient's cell phone. The amount was a significant cash shock, as it was comparable to nearly four months of an average salary. The recipients were informed that the cash came from a "foreign donor" and not from Mercy Corps. By attributing the funds to a foreign source, this could indirectly help build credibility for the current government by signaling to civilians that the government's effectiveness was responsible for attracting foreign funds.

Two weeks and eight months after they had completed the training and/or received the cash, participants were surveyed through in-person interviews on their attitudes towards the Afghan government and Taliban, and violence.

The results of the study were striking. Despite the vocational training, the program had only a modest effect in helping recipients improve their economic livelihoods. There was a 5 percent increase in both the likelihood of recipients earning cash and owning land. Employment outcomes were nominal; participants reported working just one day more per month than before they had completed the training. The intervention also did not appear to have an effect on pro-government sentiment. If anything, the intervention just raised people's expectations. With very few jobs available, supporting the Taliban became an appealing option, where they could stand to earn US $15 a day and receive other perks.

As for the cash infusion, two weeks after receiving the cash transfer, there was increased support for the Afghan government among recipients. Nine months later, however, this trend was reversed. Recipients reported anger towards the government and increased support for the Taliban. Participants had spent most, if not all of the cash on consummables and once that money was gone, their lives really had not improved.

In contrast, there was modest progress among participants who had received both the cash and the vocational training. Support for the Afghan government increased. Yet, if they received the cash or job training separately, the intervention had the adverse effect of increasing support for the Taliban rather than steering participants away from it.

"Throughout the world, the humanitarian industry is spending a tremendous amount of money in conflict areas providing job training and infusing cash; yet, there is little evidence that these aid programs work," explained Jason Lyall, the inaugural James Wright Chair in transnational studies, director of the Political Violence FieldLab and an associate professor of government at Dartmouth, who led the research project, and has conducted fieldwork in Afghanistan.

"In conflict zones, non-governmental organizations often aim to offer vocational training as a way to help civilians break into the market; yet, this approach may be flawed by creating false hope in areas that may have a struggling economy and a limited number of jobs," he added. "Cash transfers are the number one instrument used in the field for dealing with refugees, especially in conflict settings, as this type of intervention is inexpensive and has little overhead. Our research in Kandahar, Afghanistan, demonstrates how a one-time cash infusion in a war zone ultimately increased combatant support, and that from a moral point of view, is problematic," explained Lyall.

With the study's findings, the researchers hope that the humanitarian community will strive to be more rigorous in their methods before implementing aid projects in conflict zones, so as to minimize the potential for a backlash effect.