Culture

Imagine flexible surgical instruments that can twist and turn in all directions like miniature octopus arms, or how about large and powerful robot tentacles that can work closely and safely with human workers on production lines. A new generation of robotic tools are beginning to be realized thanks to a combination of strong 'muscles' and sensitive 'nerves' created from smart polymeric materials. A research team led by the smart materials experts Professor Stefan Seelecke and Junior Professor Gianluca Rizzello at Saarland University is exploring fundamental aspects of this exciting field of soft robotics.

In the factory of the future, man and machine will work side-by-side - in harmony, as a team, joining forces whenever necessary - just as if the robot co-worker was made from flesh and blood. While collaborative robots ('cobots') are already being deployed in industrial production lines, real hand-in-hand teamwork involving robots and their human counterparts is still some way off. The problem lies in the physical proximity of human co-workers, whose actions - unlike those of a robot - do not follow predictable algorithms. A human worker can become tired or distracted and may act suddenly or even illogically as a result. This has clear implications for safety and explains why the robot arms currently used on production lines are often housed in cages. For anyone who gets too close, things can get dangerous. Typically, industrial robots are large, heavy machines. But they are also powerful, fast and agile and are used for a wide range of operations, like welding, assembling, painting, stacking and lifting. However, the motions that they execute are dictated wholly by the programs that control them. And if someone gets in their way or too close, the consequences can be serious.

The team led by Professor Stefan Seelecke and Junior Professor Gianluca Rizzello of Saarland University and the Center for Mechatronics and Automation Technology (ZeMA) in Saarbrücken are working on new, smart types of robot arms. 'Our technology is based on smart polymer systems and enables us to create novel soft robotic tools that are lighter, more manoeuvrable and more flexible than the rigid components in use today,' explains Stefan Seelecke. An accidental shove from one of these robotic arms of the future would be more like being pushed by a human co-worker (and less likely to land you in hospital).

The material used for these new soft robot arms is a special kind of polymer known as a 'dielectric elastomer'. The Saarbrücken researchers are using this composite material to create artificial muscles and nerves. The special properties of dielectric elastomers make it possible to develop systems inspired by the ingenious designs found in nature. These elastomers can be compressed, but can then be stretched to regain their original shape. 'We print electrodes onto both sides of the elastomer material. When we apply a voltage, the two electrodes attract each other, compressing the polymer and causing it to expand out sideways,' says Dr. Gianluca Rizzello, Junior Professor for Adaptive Polymer-Based Systems. The Italian research scientist has been working in Seelecke's team since 2016. The elastomer can thus be made to contract and relax, just like muscle tissue. 'We exploit this property when designing our actuators,' explains Rizzello. By precisely varying the electric field, the engineers can make the elastomer execute high-frequency vibrations or continuously variable flexing motions or even remain still in a particular desired intermediate position.

The researchers then combine a large number of these small 'muscles' to create a flexible robot arm. When combined in this way to form a robot tentacle, the interplay between the muscles produces motions that mimic those of an octopus arm that can twist and turn in all directions. Unlike the heavy, rigid robotic limbs currently in use, which, like humans, can only execute motions in certain directions, these new robot tentacles are free to move in almost any direction. Gianluca Rizzello together with his doctoral student Johannes Prechtl recently won the Best Paper Award at the RoboSoft 2021 conference for their work on developing a prototype dielectric-elastomer-based tentacle - just one of the numerous accolades earned by Professor Seelecke's research team. The team hopes to have the tentacle prototype fully developed in about a year's time.

When it comes to imparting intelligence into polymeric materials, Gianluca Rizzello is something of an expert. He provides the control unit (i.e. the robot's 'brain') with the input needed to move the arm in an intelligent manner - a highly complex and ambitious task. 'These systems are significantly more complex than the robot arms in use today. Using artificial intelligence to control polymer-based components is substantially more challenging than controlling conventional mechatronic systems,' explains Rizzello. As the elastomer muscles also have sensor properties, they can act as the system's nerves, which means that the robot arm does not need to be equipped with additional sensors. 'Every distortion of the elastomer, every change in its geometry causes a change in the material's capacitance, which enables the team to assign a precise electrical capacitance value to any specific deformation of the elastomer. By measuring the capacitance, we know exactly what shape the elastomer has adopted, which allows us to extract sensor data,' explains Rizzello.

This quantitative data can then be used to precisely model and program the motion of the elastomer arm. The focus of Rizzello's research work is on developing intelligent algorithms that can train these novel robot tentacles to move and respond in the required manner. 'We are attempting to uncover which physical properties are responsible for the behaviour of these polymers. The more we know, the more precisely we can design the algorithms to control the elastomer muscles,' says Dr. Rizzello.

The technology being developed in Saarland will be scalable. It can be used to create miniature tentacles for medical instruments or to make large robot arms for industrial applications. But unlike the heavy robot arms in use today, the robot limbs built from smart elastomers will be far lighter. 'Our robot arms don't need to be driven by motors or by hydraulic or pneumatic systems - they can be powered simply by the application of an electric current. The elastomer muscles can also be produced in shapes that meet the requirements of a particular application. And they consume very little electric power. Depending on the capacitance, the electric currents that flow are in the microampere range. This type of soft robot technology has huge promise for the future as it is both energy efficient and cost-effective to manufacture,' says Stefan Seelecke in summary.

Augmented reality (AR) is poised to revolutionise the way people complete essential everyday tasks, yet older adults - who have much to gain from the technology - will be excluded from using it unless more thought goes into designing software that makes sense to them.

The danger of older adults falling through the gaps has been highlighted by research carried out by scientists at the University of Bath in the UK in collaboration with designers from the Bath-based charity Designability. A paper describing their work has received an honourable mention at this year's Human Computer Interaction Conference (CHI2021) - the world's largest conference of its kind.

The study concludes that adults aged 50+ are more likely to be successful at completing AR-prompted tasks (such as 'pick up the cube' followed by 'move the cube to the blue area') when the steps are shown by a 'ghosthand' demonstrating the action rather than the more commonly used arrow or some other visual aid.

According to the research team, many manufacturers of AR software are failing to factor the needs and preferences of older people into their application designs.

"We can't expect people to benefit from AR technology if they can't follow the prompts shown to them," said Dr Christof Lutteroth from the University's Department of Computer Science.

Thomas Williams, the Doctor of Engineering student (funded by the EPSRC) who conducted the research from the university's Centre for Digital Entertainment, said: "A lot more thought needs to go into understanding what older adults need from augmented reality, so users in this group understand the prompts they're given straight away."

He added: "AR technology has great potential for improving the lives of older adults but most AR designers give little or no thought to the kind of augmentations they use for this population."

Supervising the project were Dr Lutteroth and Dr Simon Jones, also from Bath's Department of Computer Science, Dr Elies Dekoninck from the Department of Mechanical Engineering and Dr Hazel Boyd from Designability.

For the study, participants were asked to lift, move, lower, open and close 3D shapes on a foam board in response to four different types of visual instruction displayed on a laptop that was running the AR application. Overall, participants preferred the ghosthand over other AR prompts, and were both faster at completing tasks and more confident in their actions. Assisted by the hand, they responded up to twice as fast and twice as accurately as they did when using another, more commonly used prompt. Participants commented that they could relate to the hand and it was clearer to them than the other visual prompts.

Demonstrations delivered by three other 'augmentations' - an arrow, a transparent ghost of the object and a pulsating transparent ghost - often resulted in participants hesitating before taking action and needing to see the visual instructions more often to get the task completed. It also led to participants being less sure that they'd done the job right.

"Though AR technology has great potential for improving the lives of older adults, this user group is rarely considered the target for AR development," said Dr Lutteroth. "I think this is the first study to investigate the accessibility of AR technology to older users."

HOW AR CAN HELP WITH DEMENTIA AND MEMORY PROBLEMS

Researchers envision AR technology soon being adopted to help others:

Understand what it might be like living with a cognitive impairment such as dementia

Make better assessments of fall-prevention modifications to older adults' homes

Reduce navigation- and distraction-related errors with in-car navigation systems

Provide training for improving spatial direction.

The research teams sees huge potential for AR technology being used to help people with dementia and other memory difficulties. Using AR, a task such as preparing food, hand washing or making a cup of tea can be broken down into individual steps, each step represented simply and clearly on a screen or AR glasses, making it far easier for the job to be completed successfully. AR is also being explored as a diagnostic tool to detect early signs of cognitive decline and provide people with an earlier diagnosis of dementia.

"Activities of daily living that we take for granted can be more difficult for people with dementia, and AR prompting could make a big difference for them if designed appropriately," said Dr Boyd.

INCLUSIVITY

So why are older adults being left out of AR research? "Designers often find it difficult to know how non-designers and older people think if they're not big users of tech." explained Dr Jones.

"Another common problem is that designers often prioritise in a way that's not inclusive - they worry about the aesthetics of an application more than the ease of use for everyone. This is fine if you're a regular user of an application but it violates an essential principle of usability: you shouldn't have to read a manual to achieve what you're trying to achieve."

AR is gaining popularity in medicine, cultural heritage tourism, industrial assembly, and more recently, in the home. It allows people to use their smartphones or special glasses to immerse themselves in a real-world environment where the objects in their immediate vicinity are enhanced by digital content (such as a ghosthand). Over the next decade, computer scientists expect this technology to become increasingly integrated into all our daily lives.

"We'll be using AR for everything from fixing our own washing machines to deciding whether we're better off catching the bus from bus stop 1 or 2 as we're walking down the street," said Dr Dekoninck.

According to a recent study, open learning spaces are not directly associated with the physical activity of students in grades 3 and 5, even though more breaks from sedentary time were observed in open learning spaces compared to conventional classrooms.

The findings are based on the CHIPASE study, carried out at the Faculty of Sport and Health Science of the University of Jyväskylä. The results were published in Frontiers of Sports and Active Life.

After the reform of the national core curriculum for basic education in Finland, issued in 2016, most of the new or renovated comprehensive schools in Finland began to incorporate open and flexible classroom designs and principles. Combined with student-centred pedagogies, these open learning spaces may increase children's physical activity during lessons. Classroom-based physical activity may also have a positive impact on academic-related outcomes.

"Surprisingly, students were physically less active in open learning spaces than in conventional classrooms," Says Doctoral Researcher Jani Hartikainen from Faculty of Sport and Health Sciences at the University of Jyväskylä. "In turn, open learning spaces seem to enable more breaks from sedentary time, which may decrease the potential adverse effects of prolonged sitting on the health of children."

The main result of the study was that, on their own, open learning spaces do not increase children's' physical activity during lessons. Future studies should seek to investigate and develop teacher practices to capitalise on the potential of open learning spaces to promote classroom-based physical activity.

"In this study, we did not observe teachers' instructions about students' movement, but prior studies have reported difficulties in how teachers adapt to open learning spaces," Hartikainen says. "Especially large student groups may cause teachers to need to restrict students' movement during lessons."

The relationship between personality, genes and chronotype (sleep patterns) has been studied by researchers at the University of Warwick and the University of Tartu, Estonia

People high in Conscientiousness and low in Openness are rather morning people; lower-level personality traits such as self-discipline, excitement-seeking, and straightforwardness have also been linked to chronotype

It is partly due to genetic factors, but there is scope to change your sleep patterns if you wanted to become a morning person but are currently an evening person for example

The link between the different hierarchies of personality, sleep patterns and even genetics has been discovered by researchers from the Department of Psychology at the University of Warwick.

A typical example of a morning person is thought to be someone who wakes up naturally at 6am, goes for a jog, showers, has breakfast and is ready for a productive day at work by 9am. Whereas an evening person struggles to get up in the morning and feels more productive in the evening.

Researchers from the University of Warwick with colleagues from the University of Tartu have recently had the paper, 'Personality Traits Relate to Chronotype at Both the Phenotypic and Genetic Level' published in the Journal of Personality, in which they have analysed the relationship between sleep timing (chronotype), preference to the morning/evening, and personality traits at a phenotypic and genetic level.

Ultimately the researchers have found that the relationship between personality and morningness-eveningness is partly due to genetic factors.

Using a large-scale sample of participants form the Estonian Biobank researchers asked them to answer questionnaires about their sleep timings and personality, personality was also assessed by someone who knew the participant well. Once answered researchers were able to identify the phenotypic relationships between the sleep and personality.

However they were also able to calculate the genetic correlations through summary statistics of large genome-wide association studies of personality and sleep preferences.

Personalities can be divided into three hierarchies: personality domains, facets and items, researchers analysed all three, but in particular they found on a domain level that people high in Conscientiousness and low in Openness were associated with being earlier chronotypes (i.e., they went to bed and got out of bed earlier).

On a facet level, researchers found that less straightforward (a facet of Agreeableness) and excitement-seeking (a facet of Extraversion), yet more self-disciplined (a facet of Conscientiousness) people were more likely to have earlier chronotypes. Higher Conscientiousness and lower Openness were also genetically related to preference for morningness.

Postgraduate researcher Dr Anita Lenneis, from the Department of Psychology at the University of Warwick comments:

"Our findings have helped us to come up with two possible pathways of how personality might influence chronotype. Personality traits such as Conscientiousness and C5: Self-discipline in particular may influence chronotype through shaping people's preferences for various social activities and behaviours which in turn, may influence what time people go to and get out of bed, or personality may influence chronotype is through active decisions people make regarding their sleep.

"However, it could also be that chronotype influences personality or that chronotype and personality mutually influence each other. The findings of the genetic correlations support this view but further studies will be necessary to better understand the shared genetic mechanisms between the two constructs as well as the causality of their relationships."

Professor Anu Realo, from the Department of Psychology at the University of Warwick adds:

"Not only have we shown there is a relationship between chronotype, personality and partially your genes, our findings also suggest that it might be possible to change your chronotype or at least train yourself into a different more socially convenient sleep pattern by increasing your self-control. Ideally work hours would be adapted to your chronotype, but if not, evening people who typically experience worse health could learn to go to bed at earlier hours which might also accelerate the release of melatonin. Melatonin is also influenced by artificial light, so regularly turning off the lights at earlier hours might also lead to falling asleep at earlier hours of the evening. However, future studies will need to investigate whether such interventions to enhance self-control would result in a permanent change or would indeed promote better health in later chronotypes."

Most of us have genetic variations that increase the risk of medicinal products not being effective. In order to provide a more effective treatment with fewer side effects, we need to analyse more of these genetic variations. This will provide us with more precise knowledge about how the individual patient reacts to medicinal products. A new research result from Aarhus University shows that.

Personalised medicine has been a hot topic in recent years, using information about the genes to adapt the treatment to the individual patient. Personalised medicine potentially provides better treatment and fewer side effects for the patient. At least in an ideal world.

How the body converts medicinal products - the scientific term is metabolises - is also affected - among other factors - by our genes, among other factors. Research from Aarhus University now shows that more than eighty per cent of the participants in a study based on data from the National Psychiatry Project iPSYCH, have more than three genetic variants, which increase the potential risk of the medicinal products not having the effect they should.

"Pharmacogenetic variation can impact how we metabolise or react to drugs compared with the average patients. Rapid metabolism can increase the risk of a reduced effect of medicine, and slow metabolism can increase the risk of an 'overdose' that can be experienced as side effects," explains Christiane Gasse from Aarhus University, who is leading the study.

Not only applicable to medicine for mental disorders

The researchers have analysed the frequency of genetic variants in clinically relevant drug metabolism or drug targets of 51,464 people with a diagnosed mental disorder and 26,220 without - a total of 77,684 people.

"The study has primarily analysed pharmacogenetic variants with documented recommendations of dose adjustment having great importance for the effect of the affected drugs. Many of these drugs are psychotropic medications - i.e. medicine for people with a mental disorder, but include also drugs for cardiovascular disorders. We found that more than 80% of the analysed population had more than three pharmacogenetic variants that potentially affect the metabolism of these drugs," she says.

Criteria for how the medication and dose work most effectively on the majority of the population defines the dosage of a medicine. However, the desired effect is not achived in some cases, or or patients experience side effects. Individualized treatment with medicinal products may include a pharmacogenetic test, in which the patient's genes are analysed. Based on the patient's genetic profile, it is possible to determine how effectively the actual medicine is metabolised in the individual patient.

"Most often there are several genes and genetic variants that influence the effect of the medicine. Within all medicinal products, we know of 42 variants where international pharmacogenetic consortia have described recommendations about pharmacogenetic guided dosing. They are therefore relevant for adjustments, and are therefore relevant for clinical practice," explains Christiane Gasse.

Now, genetic tests often analyse a single genetic variation, which is known to have an effect on the metabolism of the drug in question. However, the researchers believe that it would be possible to obtain far more accurate information about the patient's disposition to metabolise medicines, if more genetic variants were analysed.

The solution is a wide-ranging panel test that can analyse several pharmacogenetic variations at the same time and in this way provide the opportunity to plan more optimal treatment.

"The study demonstrates the need to use a pharmacogenetic test that analyses a wide range of genes and genetic variants. This can provide information about the choice of the right medicinal product or the right dose for the individual patient", says Christiane Gasse.

She adds that a pharmacogenetic test can either be performed prior to the first treatment with a relevant drug, and can be used as guidance for the planned and future treatments, or it can be done during the course of treatment with aim to adjust the dose and if needed the medicine.

The spinal cord is an important component of our central nervous system: it connects the brain with the rest of the body and plays a crucial part in coordinating our sensations with our actions. Falls, violence, disease - various forms of trauma can cause irreversible damage to the spinal cord, leading to paralysis, sometimes even death.

Although many vertebrates, including humans, are unable to recover from a spinal cord injury, some animals stand out. For instance, the axolotl (Ambystoma mexicanum), a salamander from Mexico, has the remarkable ability to regenerate its spinal cord after an injury. When an axolotl's tail is amputated, neural stem cells residing in the spinal cord are recruited to the injury to rebuild the tail. So far, scientists could only detect this activity a few days after the process had started.

"Four days after amputation, stem cells within about one millimetre of the injury divide three times as fast as the normal rate to regenerate the spinal cord and replace lost neurons," explains Emanuel Cura Costa, co-first author of the study. "What the stem cells are doing in the first four days after injury was the real mystery."

To understand what happens in the first moments of spinal cord regeneration, researchers at CONICET, IMP, and TU Dresden teamed up to recreate the process in a mathematical model and test its predictions in axolotl tissue with the latest imaging technologies. Their findings, published in eLife, show that neural stem cells accelerate their cell cycles in a highly synchronised manner, with the activation spreading along the spinal cord.

Regenerating in sync: cells follow the tempo

In the uninjured spinal cord, cells multiply asynchronously: some are actively replicating their DNA before splitting into two cells to sustain growth, while some are simply resting.

The scientists' model predicted that this could change dramatically upon injury: most cells in the vicinity of the injury would jump to a specific stage of the cell cycle to synchronise and proliferate in unison.

"We developed a tool to track individual cells in the growing spinal cord of axolotls. Different colours label resting and active cells, which allow us to see how far and how fast cell proliferation happens with a microscope," says Leo Otsuki, postdoc in the lab of Elly Tanaka at the IMP and co-first author of this study. "We were very excited to see the match between the theoretical predictions and the experimental results."

The way cells multiply in chorus in the regenerating spinal cord is exceptional in animals. How can cells coordinate their efforts over almost one millimetre - 50 times the size of a single cell?

A mystery signal orchestrating regeneration

"Our model made us realise there had to be one or more signals that spread through the tissue from the injury, like a wave, for the area of proliferating cells to expand," explains Osvaldo Chara, career researcher at CONICET, group leader of SysBio at the Institute of Physics of Liquids and Biological Systems (IFLySIB) and guest professor at Center for Information Services and High Performance Computing (ZIH), Technische Universität Dresden. "This signal might act like a messenger and instruct stem cells to proliferate."

The researchers suspect that this mystery messenger helps reprogram stem cells to divide rapidly and regrow amputated tissue. Their work pinpoints this signal in space and time, and paves the way to characterise it further.

"Combining mathematical models with our expertise in tissue imaging was key to understanding how the spinal cord starts regenerating," says Elly Tanaka, senior scientist at the IMP. "The next step is to identify the molecules that promote regeneration of the spinal cord - that could have tremendous therapeutic potential for patients with spinal injuries."

Researchers have identified a combination of biological markers in patients with dengue that could predict whether they go on to develop moderate to severe disease, according to a study published today in eLife.

Biomarkers are used to identify the state or risk of a disease in patients. Examples of biomarkers can include naturally occurring molecules or genes in the vascular, inflammatory or other biological pathways. The new findings could aid the development of biomarker panels for clinical use and help improve triage and risk prediction in patients with dengue.

Dengue is the most common mosquito-borne viral disease to affect humans globally. In 2019, the World Health Organization identified dengue as one of the top 10 threats to global health, with transmission occurring in 129 countries and an estimated 3.9 billion people being at risk.

"While most symptomatic dengue infections are self-limiting, a small number of patients develop complications that usually occur at around four to six days from symptom onset," explains first author Vuong Nguyen Lam, Researcher and PHD Student at Oxford University Clinical Research Unit (OUCRU), Ho Chi Minh City, Vietnam. "Large numbers of patients therefore need regular assessments to identify these complications. The accurate and early identification of such patients, particularly within the first three days of illness, should allow for the appropriate care to be provided."

The role of blood biomarkers in predicting severe outcomes has been investigated in other studies, but mostly later in the disease progression or at hospital admission. Many of these biomarkers either peak too late in the disease course or have too short a half-life to be clinically useful.

To address this, Vuong and colleagues selected 10 candidate biomarkers from vascular, immunological and inflammatory pathways that are associated with dengue disease pathogenesis. These biomarkers were: VCAM-1, SDC-1, Ang-2, IL-8, IP-10, IL-1RA, sCD163, sTREM-1, ferritin, and CRP. They were chosen based on their likelihood to be increased during the early stages of disease.

The team then conducted a study using samples and clinical information from a large multi-country observational study called 'Clinical evaluation of dengue and identification of risk factors for severe disease' (IDAMS study). Of the 2,694 laboratory-confirmed dengue cases included in the IDAMS study, 38 and 266 cases were classified as severe and moderate dengue, respectively.

For the current study, the researchers selected 281 cases in four countries - Vietnam, Cambodia, Malaysia and El Salvador - as the blood samples from these participants were stored at the OUCRU laboratory. For comparison, the team also selected 556 patients with uncomplicated dengue who shared similar geographies and demographic characteristics.

They measured the participants' blood biomarkers at two different time points - one during the first three days of illness, and the second following recovery (10-31 days after symptom onset). They found that, during the first three days of illness, higher levels of any of the 10 biomarkers increased a patient's risk of developing moderate to severe dengue.

They also identified a combination of six biomarkers that was best associated with severe disease in children, and a combination of seven biomarkers that was best associated with severe disease in adults. "This highlights how relationships between biomarkers and clinical outcome can differ between age groups," Vuong says.

"Together, our findings should assist the development of biomarker panels to help improve future triage and early assessment of dengue patients," concludes senior author Sophie Yacoub, Dengue Research Group Head at OUCRU. "This would help improve individual patient management and healthcare allocation, which would be of major public health benefit especially in outbreak settings."

HOUSTON - (June 22, 2021) - How do you kill tumor cells that can't be targeted? Get their more susceptible neighbors to help.

The Rice University lab of synthetic chemist K.C. Nicolaou, in collaboration with AbbVie Inc., has created unique antibody-drug conjugates (ADCs) that link a synthetic uncialamycin analogue to antibodies that target cancer cells.

Once they enter the targeted tumor cells, these ADCs exhibit a "significant bystander effect," according to the study. In other words, cancerous neighbor cells that aren't directly attacked by the drugs are also affected.

The study in the Proceedings of the National Academy of Sciences presents "an intriguing opportunity in the tumor-targeting therapeutics development area," according to the researchers.

"The bystander effect is expected to improve the efficacy of the ADC drug by killing, in addition to the targeted cancer cells, a significant number of nearby, nontargeted cancer cells usually found within or in close proximity to malignant tumors," Nicolaou said.

Nicolaou's lab, which specializes in the synthesis of molecules found in nature that have medicinal properties, first reported in 2016 its development of a method to simplify its synthesis of uncialamycin, an enediyne compound isolated from a strain of marine bacteria. Once inside the nucleus of a cell, it produces radicals that cut both strands of the target's DNA.

The earlier study produced 13 analogues of uncialamycin and tested them on lung, gastric, ovarian and multidrug-resistant cancer cell lines with "remarkably high potency," the researchers reported at the time, suggested they showed promise as ADC payloads and chose one for further development.

That promise is now paying off. In tests on solid tumors, the best of a variety of ADCs killed not only the cell that expressed the target protein but also "neighbor" cancer cells that didn't.

"That is unique within the enediyne payload-carrying ADCs, and in contrast to the currently employed ADCs containing N-acetyl calicheamicin payloads, which do not exhibit this killing effect," Nicolaou said.

Importantly, he said, the majority of clinically approved ADCs demonstrate bystander killing effect.

The study found ADCs made with cleavable linkers that are stable in the bloodstream but release their payloads in the tumor microenvironment were most effective at decreasing the size of small-cell lung cancer tumors in PDX mouse models.

An enzyme found in fat tissue in the centre of our bones helps control the production of new bone and fat cells, shows a study in mice published today in eLife.

The findings may help scientists better understand how the body maintains fat stores and bone production in response to changing conditions, such as during aging. They may also suggest new approaches to treating conditions that cause bone loss in older adults.

Fat cells, including those found in the bone marrow, are increasingly recognised as an important part of the body that helps regulate body weight, insulin sensitivity and bone mass. Fat tissue in the bone marrow expands as people age, or when they take certain diabetes medications, and during prolonged fasting.

"This expansion of bone marrow fat is strongly associated with bone loss in mice and humans," explains lead author Nicole Aaron, PhD, a graduate student at Columbia University Vagelos College of Physicians and Surgeons, New York, US. "But how these changes occur is still not well understood."

Aaron and her colleagues conducted a series of experiments to explore these processes further. They fed mice a calorie-restricted diet and found that this caused fat in their bone marrow to grow and increased the production of an enzyme called adipsin. The levels of adipsin were also high in mice treated with a diabetes drug called rosiglitazone, which increases bone marrow fat and decreases bone mass. Aging also caused similar changes in the animals.

The team then carried out similar experiments in mice that were genetically engineered to lack adipsin. They found that the animals were resistant to these changes, and had less bone marrow fat and stronger bones. Specifically, these experiments showed that adipsin appears to cause stem cells in the bone marrow to develop into fat cells rather than bone cells.

"Similarly, results from our human studies also revealed that the expansion of bone marrow fat with fasting was associated with a marked increase in adipsin and evidence of bone breakdown," says author Clifford Rosen, Director of Clinical and Translational Research at Maine Medical Center, Portland, Maine, US. "These findings may help explain the link between expansion of bone marrow fat tissue and bone strength, particularly during aging."

Drugs that block adipsin are currently being developed to treat people with a form of age-related vision loss. The current study also suggests these drugs might help increase bone mass in older people with diseases such as osteoporosis that cause progressive bone loss.

"There is the potential for these existing treatments to be repurposed to treat and prevent age-related skeletal disorders," concludes senior author Li Qiang, PhD, Assistant Professor of Pathology and Cell Biology at Columbia University Vagelos College of Physicians and Surgeons. "These treatments could also potentially be targeted to individuals who develop bone loss as a result of eating disorders, such as anorexia, or aging."

DETROIT - Jessica Damoiseaux, Ph.D., an associate professor with the Institute of Gerontology at Wayne State University, recently published the results of a three-year study of cognitive changes in older adults. The team followed 69 primarily African American females, ages 50 to 85, who complained that their cognitive ability was worsening though clinical assessments showed no impairments. Three magnetic resonance imaging scans (MRIs) at 18-month intervals showed significant changes in functional connectivity in two areas of the brain.

"An older adult's perceived cognitive decline could be an important precursor to dementia," Damoiseaux said. "Brain alterations that underlie the experience of decline could reflect the progression of incipient dementia and may emerge before cognitive assessment is sensitive enough to detect a deficit."

The resulting paper, "Longitudinal change in hippocampal and dorsal anterior insulae functional connectivity in subjective cognitive decline," appeared in the May 31 issue of Alzheimer's Research & Therapy. Damoiseaux conducted the study with graduate student Raymond Viviano, Ph.D., who is first author.

Subjective cognitive decline, defined as a perceived worsening of cognitive ability not noted on clinical assessment, may be an early indicator of dementia. Previous cross-sectional research has demonstrated aberrant brain functional connectivity in subjective cognitive decline, but longitudinal evaluation has been limited.

Viviano and Damoiseaux's three-year study found that persons reporting more subjective cognitive decline showed a larger decrease in connectivity between components of the default mode network and a larger increase in connectivity between salience and default mode network components. The functional connectivity changed in the absence of a change in cognitive performance.

Since these brain changes occurred without concomitant cognitive changes, they could indicate that brain changes underlie the perception of decline. These changes could be a sensitive marker for nascent dementia months or years before assessments detect any cognitive deficit.

(Boston)--Lung cancer remains the leading cause of cancer-related deaths. Non-small cell lung cancer (NSCLC) accounts for 80-85 percent cases of lung cancer and when diagnosed early, has a five-year survival rate of 50-80 percent. Black patients have lower overall incidence of NSCLC than white patients, but are more likely to be diagnosed at later stages. They also are less likely to receive surgery for early-stage cancer.

Now a new study from Boston University School of Medicine (BUSM) highlights the impact that structural racism and residential segregation has on NSCLC outcomes.

The researchers analyzed patient data from the Surveillance, Epidemiology and End Results Program--a database of Black and white patients diagnosed with NSCLC from 2004-2016 in the 100 most populous counties. They found that Black lung cancer patients living in the most segregated U.S. counties were 49 percent more likely to be diagnosed at an advanced stage, compared to those living in the least segregated counties. Among those with early-stage lung cancer, Black patients in highly segregated areas were 47 percent less likely to receive surgery. Segregation was used in this study as a proxy for historic housing discrimination and the enduring structural racism that has resulted from it.

"Our study suggests that Black patients have a greater likelihood of presenting at advanced stage than their white counterparts, a disparity that disappears at low levels of segregation. Similarly, higher residential segregation is associated with increased risk of advanced stage for Black patients but not white. This may be due to factors such as lack of access to routine medical care and lack of routine screenings for Black patients in segregated areas," explained corresponding author Kei Suzuki, MD, assistant professor of surgery at BUSM.

According to the researchers, fewer Black patients are considered eligible for lung cancer screening criteria and also are less likely to complete screening. For many diseases including lung cancer, Black patients of lower socioeconomic status tend to present to their physician only when symptomatic, aligning with a later stage of disease.

"Broadly, urban policy can serve to address the structural factors leading to these outcomes. Most immediately, clinicians and healthcare institutions can focus screening efforts in these minoritized communities and realize the racialized socioeconomic implications that may impact access to care, which may delay definitive care," adds Suzuki, who also is a thoracic surgeon at Boston Medical Center.

These findings appear online in the journal Annals of Thoracic Surgery and was presented virtually as an oral presentation at the Society of Thoracic Surgery 2021 Annual Meeting on Jan. 31, 2021.

PROVIDENCE, R.I. [Brown University] -- What motivated Americans to wear masks and stay socially distanced (or not) at the beginning of the COVID-19 pandemic? More often than not, it was partisanship, rather than perceived or actual health risk, that drove their behavior, according to a new study co-authored by researchers at Brown University.

By analyzing the results of two online surveys of more than 1,100 adults in total, Mae Fullerton, a Class of 2021 Brown graduate, and Steven Sloman, a professor of cognitive, linguistic and psychological sciences, found that in spring and fall 2020, political partisanship was the strongest predictor of whether someone would wear a mask or practice social distancing to stem the spread of novel coronavirus.

Those who identified as liberal or moderate overwhelmingly said they wore masks and practiced social distancing, even when they believed their risk of contracting the novel coronavirus was minimal. Those who identified as conservative were much less likely to say they always wore a mask or socially distanced, even when they believed they were at high risk of contracting the virus and falling ill with COVID-19.

The findings were published on Friday, June 18, in the Journal of Health Psychology. Sloman said the results show that many Americans tend to remain fiercely loyal to their like-minded communities, even in situations where their health is on the line.

"It turns out that life is not the most important thing to people," Sloman said. "Many people are putting their partisan leanings ahead of their self-interest. We're willing to outsource our thinking to other people in our communities, even when our lives are at stake."

At the start of the study, Fullerton and Sloman predicted that respondents' risk of becoming sick with COVID-19, or at least their perception of risk, would be the primary factor guiding their mask uptake and social distancing. Instead, they found almost no correlation between behavior and risk -- whether perceived or real. Among survey respondents who considered themselves to be at high risk of contracting COVID-19, 59% reported they had limited their encounters to two or fewer people in the prior week. Meanwhile, among those who perceived they were at low risk of contracting COVID-19, 58% reported the same. In other words, people who felt they were in a high-risk group didn't seem any more likely to practice social distancing than their lower-risk peers.

The same was true of mask-wearing: 62% of those who reported that they were elderly or had no health insurance said they always wore masks when they anticipated coming within 6 feet of others, compared to 61% of those who were younger and had health insurance.

They found, in fact, that the biggest predictor of whether someone was likely to wear a mask and practice social distancing wasn't risk but political partisanship. Among those who identified as liberal or moderate, 66% reported that they always wore masks when they anticipated coming within 6 feet of others, compared to 45% of those who identified as conservative. And while 95% of self-identified liberals and moderates said they thought it was important to wear a mask to prevent the spread of the virus, only 74% of self-identified conservatives said they believed the same. Conservative-leaning respondents were also significantly less likely to practice social distancing (31%) than their moderate or liberal counterparts (49%).

Crucially, the researchers also found a high correlation between compliance with stay-at-home orders -- which were in effect for 95% of Americans at the time of the survey -- and peer agreement. Among those who said they believed it was "extremely important" to comply with orders to stay socially distanced, 86% said their peer group reportedly held similar views.

Fullerton said the findings confirm something behavioral scientists have known for a long time: that most people's health decisions have more to do with the behaviors of people around them than with scientific evidence. Studies have shown, for example, that people are more likely to quit smoking if someone close to them has quit smoking recently, and that the amount of food a person eats on Thanksgiving is often driven by how much others at the table are eating.

"This study supports other findings that preventive behavior is strongly influenced by social norms," Fullerton said. "People clearly are more motivated by their politics, their culture and their peers than by their likelihood of catching the virus and possibly suffering from terrible side effects. This suggests that communicating the risks of not wearing a mask and not staying socially distanced might not be the most effective way to stop the spread of a virus."

Both Fullerton and Sloman said the reason many conservative Americans didn't wear masks and socially distance may be in part because the people they trusted most -- people who include, according to past studies, family doctors, local television hosts and church leaders -- weren't wearing masks or staying distanced either. Getting buy-in from influential community figures, then, may be key in ensuring more unified compliance with public health recommendations in the future. And that might start with bringing more widely known trusted personalities on board, from television hosts to beloved celebrities to leading federal lawmakers.

"In some cases, communicating the risks via government-appointed experts might not be as effective as communicating the risks via political leaders people know and respect," Fullerton said. "That's a good lesson we can remember the next time we're facing a public health crisis."

Ultimately, both Fullerton and Sloman said, the key to keeping people safe and healthy is understanding their most sacred values. For example, Sloman said, many libertarians didn't refuse to wear masks just because some of their local politicians vocally opposed masking; some perhaps did it because individual freedom is their most sacred value, and they believed mask mandates infringed on that freedom. Many older people at high risk of severe COVID-19 due to other health challenges, Fullerton said, may have chosen not to practice social distancing because, to them, the costs -- not meeting a new grandchild, for example -- outweighed the benefits -- potentially living a few years longer.

"Americans can't be boiled down to figureheads and followers or believers and non-believers," Sloman said. "Getting into people's heads is complicated, but it matters."

Other study contributors were Nathaniel Rabb, a project manager at the Policy Lab at Brown; Sahit Mamidipaka, a student at Northview High School in Georgia; and Lyle Ungar, a professor of computer and information science at the University of Pennsylvania. The research was supported in part by a donation from Adobe.

New research published in the Journal of Medicinal Food suggests eating prunes each day can improve risk factors for cardiovascular disease (CVD) including raising antioxidant capacity and reducing inflammation among healthy, postmenopausal women.

Cardiovascular disease is the number one cause of death worldwide posing a significant public health challenge.

The research led by San Diego State University reveals that prunes can positively affect heart disease risk.

"When you look at our prior research and the research of others combined with this new data, you'll see consistent evidence that eating prunes can promote health," said lead researcher Shirin Hooshmand, Ph.D., RD, Professor at the School of Exercise and Nutritional Sciences at San Diego State University.

In this randomized, controlled study, researchers found that eating 50 grams of prunes (about 5-6 prunes) each day for just 6 months resulted in improved CVD risk biomarkers - including raising the body's "good" cholesterol, known as HDL, and lowering the ratio of total cholesterol to HDL.

Eating prunes daily also promoted higher antioxidant capacity and lowered levels of the inflammatory cytokines interleukin-6 and tumor necrosis factor-alpha associated with CVD risk. Notably, body mass index and weight of the study participants were maintained during the trial despite adding prunes to the usual diet.

Researchers recruited 48 healthy, postmenopausal women who were divided into three groups - a control group who ate no prunes, and two treatment groups who consumed either 50 grams or 100 grams of prunes daily, throughout the six-month study. All other aspects of the women's diets and lifestyles remained similar to before the study. Various biomarkers of CVD risk were collected at the beginning and conclusion of the study to determine if there were any improvements in those biomarkers among those who consumed prunes. Interestingly, there were some similar positive results among those who ate 50 grams of prunes and those consuming 100 grams - suggesting that adding 5-6 prunes or more into the daily diet may have a positive effect on CVD risk.

"Reducing chronic inflammation and increasing antioxidant capacity in the body is associated with lower risk of CVD, along with many other diseases," said Mark Kern, Ph.D., RD, CSSD, Professor of Nutrition at the School of Exercise and Nutritional Sciences at San Diego State University. "Not only does this study show that prunes may be a good way to reduce inflammation and increase antioxidant capacity, it also suggests that eating prunes every day may improve cholesterol levels in postmenopausal women."

While the precise mechanisms and specific compounds that contribute to these beneficial effects have yet to be determined, naturally occurring antioxidant-powered phenolic compounds, fiber and other nutrients are thought to play a role. This study demonstrates that prunes may be a promising and convenient addition to the diet to reduce CVD risk and inflammation, while also improving antioxidant capacity.

The study adds to a growing body of evidence about the overall health and nutrition benefits of prunes, including bone health. Previous clinical research demonstrates a favorable bone response to prunes among postmenopausal women. Most recently, researchers reported that total bone mineral density increased in a postmenopausal woman with osteopenia after she consumed 50 grams of prunes daily for 16 months. This case study was published in the Bone Reports in May of this year.

Almost all cells in our body contain a nucleus: a somewhat spherical structure that is separated from the rest of the cell by a membrane. Each nucleus contains all the genetic information of the human being. So it serves as a kind of library - but one with strict requirements: If the cell needs the building instructions for a protein, it won't simply borrow the original information. Instead, a transcript of it is made in the nucleus.

The machinery required for this is very complex, not least because the transcripts are not simple copies. In addition to essential information, genes also contain numerous passages of meaningless "garbage". They are removed when the transcript is made. Biologists call this editorial revision "splicing".

"An important role in splicing is played by the SMN complex, a 'molecular machine' consisting of nine different proteins," explains Prof. Dr. Oliver Gruss from the Institute of Genetics at the University of Bonn, who is also a member of the university's transdisciplinary research area "Life and Health". "Interestingly, these machines are not evenly distributed in the nucleus. Instead, they accumulate at specific sites called Cajal bodies." However, there are no transport mechanisms in the cell nucleus that bring the SMN complexes to Cajal bodies. Instead, the SMN proteins themselves have certain properties that are responsible for their aggregation. Which ones these are, was unclear until now.

SMN complexes carry an unusually large number of phosphate groups

SMN complexes have a prominent feature: They carry an unusually large number of phosphate groups, which are small molecular residues with a phosphorus atom in the center. "We suspected that this phosphorylation promotes their mass clustering into Cajal bodies," explains Dr. Maximilian Schilling from the research group around Oliver Gruss.

Phosphate groups are not part of the actual blueprint of a protein - they are added later and can also be removed again. This is often how the cell regulates the activity of the respective protein. The phosphate group is attached in this process by certain enzymes, the kinases. "We have now inhibited each of the hundreds of human kinases individually and looked at how that affects the formation of Cajal bodies," Schilling says.

In this way, they encountered a network of kinases, which, when inhibited, caused the Cajal bodies to largely disappear. Further analyses showed that in the absence of these kinases, phosphorylation of SMN complexes at specific sites decreased sharply. This then causes the flash mobs in the nucleus to cease - the Cajal bodies disintegrate. The finding is particularly interesting because the kinases identified not only regulate splicing, but also the translation of the gene transcripts edited in this way into proteins. These are therefore enzymes that are crucial for various steps in this vital process.

Mutation causes severe disease

The SMN complex is known to human geneticists not only for its role in splicing: Individual mutations in its blueprint result in a serious disease, spinal muscular atrophy, in those affected. One in about 6,000 newborns is born with this genetic defect. Treatment is extremely expensive; the cost per patient runs into millions. "Some of the gene defects that cause spinal muscular atrophy are near the phosphorylation sites of the SMN complex," explains Gruss. "Affected individuals may therefore have impaired attachment of phosphate groups to these sites, and consequently also impaired formation of Cajal bodies. We suspect that this causes splicing to be impaired, which subsequently results in the disease symptoms."

The kinases identified may therefore also be suitable as a starting point for new therapies. Preliminary results from mouse model cells for human spinal muscular atrophy show that agents that increase kinase activity also improve Cajal body formation. "It is completely unclear whether these agents also ameliorate pathological changes in a complex organism," cautions Gruss against inflated expectations. "That new treatment options will eventually emerge from this is therefore still speculation at this stage."

The most comprehensive molecular study to date of the brains of people who died of COVID-19 turned up unmistakable signs of inflammation and impaired brain circuits.

Investigators at the Stanford School of Medicine and Saarland University in Germany report that what they saw looks a lot like what's observed in the brains of people who died of neurodegenerative conditions such as Alzheimer's disease and Parkinson's disease.

The findings may help explain why many COVID-19 patients report neurological problems. These complaints increase with the severity of infection with SARS-CoV-2, the virus that causes COVID-19. And they can persist as an aspect of "long COVID," a long-lasting disorder that sometimes arises following infection. About one-third of individuals hospitalized for COVID-19 report symptoms of fuzzy thinking, forgetfulness, difficulty concentrating and depression, said Tony Wyss-Coray, PhD, professor of neurology and neurological sciences at Stanford.

Yet the researchers couldn't find any signs of SARS-CoV-2 in brain tissue they obtained from eight individuals who died of the disease. Brain samples from 14 people who died of other causes were used as controls for the study.

"The brains of patients who died from severe COVID-19 showed profound molecular markers of inflammation, even though those patients didn't have any reported clinical signs of neurological impairment," said Wyss-Coray, who is the D. H. Chen Professor II.

Scientists disagree about whether SARS-CoV-2 is present in COVID-19 patients' brains. "We used the same tools they've used -- as well as other, more definitive ones -- and really looked hard for the virus's presence," he said. "And we couldn't find it."

A paper describing the study will be published June 21 in Nature. Wyss-Coray shares senior authorship with Andreas Keller, PhD, chair of clinical bioinformatics at Saarland University. The lead authors are Andrew Yang, PhD, a postdoctoral scholar in Wyss-Coray's group, and Fabian Kern, a graduate student in Keller's group.

Blood-brain barrier

The blood-brain barrier, which consists in part of blood-vessel cells that are tightly stitched together and blob-like abutments created by brain cells' projections squishing up against the vessels, has until recently been thought to be exquisitely selective in granting access to cells and molecules produced outside the brain.

But previous work by Wyss-Coray's group and by others has shown that bloodborne factors outside the brain can signal through the blood-brain barrier to ignite inflammatory responses inside the brain. This could explain why, as Wyss-Coray and his colleagues have discovered, factors in young mice's blood can rejuvenate older mice's cognitive performance, whereas blood from old mice can detrimentally affect their younger peers' mental ability.

On hearing reports of enduring neurological symptoms among some COVID-19 patients, Wyss-Coray became interested in how SARS-CoV-2 infection might cause such problems, which resemble those that occur due to aging as well as to various neurodegenerative diseases. Having also seen conflicting reports of the virus's presence in brain tissue in other studies, he wanted to know whether the virus does indeed penetrate the brain.

Brain tissue from COVID-19 patients is hard to find, Wyss-Coray said. Neuropathologists are reluctant to take the steps required to excise it because of potential exposure to SARS-CoV-2 and because regulations often prohibit such procedures to prevent viral transmission. But Keller, who has worked in the Wyss-Coray lab as a visiting professor at Stanford, was able to access COVID-19 brain-tissue samples from autopsies conducted at the hospital that's associated with Saarland University.

Using an approach called single-cell RNA sequencing, the scientists logged the activation levels of thousands of genes in each of 65,309 individual cells taken from brain-tissue samples from the COVID-19 patients and the controls.

In neurons of the cerebral cortex, signs of distress

Activation levels of hundreds of genes in all major cell types in the brain differed in the COVID-19 patients' brains versus the control group's brains. Many of these genes are associated with inflammatory processes.

There also were signs of distress in neurons in the cerebral cortex, the brain region that plays a key role in decision-making, memory and mathematical reasoning. These neurons, which are mostly of two types -- excitatory and inhibitory -- form complex logic circuits that perform those higher brain functions.

The outermost layers of the cerebral cortex of patients who died of COVID-19 showed molecular changes suggesting suppressed signaling by excitatory neurons, along with heightened signaling by inhibitory neurons, which act like brakes on excitatory neurons. This kind of signaling imbalance has been associated with cognitive deficits and neurodegenerative conditions such as Alzheimer's disease.

An additional finding was that peripheral immune cells called T cells, immune cells that prowl for pathogens, were significantly more abundant in brain tissue from dead COVID-19 patients. In healthy brains, these immune cells are few and far between.

"Viral infection appears to trigger inflammatory responses throughout the body that may cause inflammatory signaling across the blood-brain barrier, which in turn could trip off neuroinflammation in the brain," Wyss-Coray said.

"It's likely that many COVID-19 patients, especially those reporting or exhibiting neurological problems or those who are hospitalized, have these neuroinflammatory markers we saw in the people we looked at who had died from the disease," he added. It may be possible to find out by analyzing these patients' cerebrospinal fluid, whose contents to some extent mirror those of the living brain.

"Our findings may help explain the brain fog, fatigue, and other neurological and psychiatric symptoms of long COVID," he said.