Culture

When blood flow to the brain is somehow reduced or restricted, a person can suffer what we know as a stroke (from "ischemic stroke" in medical jargon). Stroke is one of those conditions that seems fairly common. This isn't a misperception: just in Europe, there are over 1.5 million new cases each year.

Some strokes can be lethal, and when they're not they often result in serious damage to the victim's ability to move. In fact, stroke is one of the major causes of long-term disability today. Recovery can be a long and arduous road. Again, in Europe, under 15% of the patients achieve full recovery, leaving 3.7 million patients with persistent impairments. Clearly, this is a medical problem that needs urgent addressing.

But rehabilitation is a complicated problem to solve. Strokes can occur in different parts of the brain, affecting different brain systems, and patients who undergo rehabilitation show a "heterogeneity in outcome", which is the medical way of saying that recovery can be very different between individual stroke victims.

"The key is to find the optimal neuro-rehabilitative strategy to maximize individual treatment outcome," says Professor Friedhelm Hummel, a neuroscientist and Director of the Defitech Chair for Clinical Neuroengineering at EPFL's School of Life Sciences. "If we want to address these challenges in everyday clinical practice, we have to first enhance our ability to predict the individual courses of recovery" adds Dr Philipp J. Koch, the study's first author.

Hummel has now led an international team of scientists into a new approach for outcome prediction that can significantly improve stroke treatment. Publishing in the journal Brain, they demonstrate a predictive method based on two powerful, cutting-edge tools: connectomes and machine learning.

The team included scientists from Sungkyunkwan University School of Medicine (Professor Y.-H. Kim), University Medical School of Geneva (Professor A. Guggisberg), Inserm Paris (Professor C. Rosso), Santa Lucia Foundation IRCCS, Rome (Professor G. Koch), and EPFL (Professor Thiran).

What is a connectome? Simply put, it's a map of a brain's wiring. The term itself was coined independently in 2005 by two scientists (one from Lausanne's University Hospital) to describe the "blueprint" of how a brain's neurons connect to each other, evoking the concept of the genome - hence, "connectome".

Connectomes are generated by analyzing multiple images taken from magnetic resonance imaging and reconstructing the brain's structural or functional wiring non-invasively and in vivo. Today, connectomes are indispensable tools for neuroscientists, especially when they want to interpret structural or dynamic brain data and associate them with functions, functional deficits, or recovery processes. In short, the connectome shows how the brain is wired to control the body and its functions, which makes them important for working out the best recovery approach for a stroke victim.

In the study, Hummel's group analyzed connectomes from 92 patients two weeks after the stroke, tracking connectome changes up to three months later while assessing motor impairment with a standardized scale. This allowed them to monitor connection changes in the individual brains of the patients while they underwent recovery.

The scientists input the connectome information into a "support-vector machine", or SVM, which is a type of machine-learning model that uses examples to map an input onto an output. SVMs are particularly useful for classification, where they tell things apart and categorize them appropriately, e.g. spam and non-spam email.

In this study, the researchers trained the SVMs to distinguish between patients with natural recovery from those without based on their whole-brain structural connectomes. The SVMs then defined the underlying brain-network pattern of each patient, focusing on those who were severely impaired to make predictions about their recovery potential, with the accuracy of each prediction cross-validated internally and externally with independent datasets.

The result is a cutting-edge tool of personalized medicine: a machine-learning system that can identify neuronal network patterns to make high-accuracy predictions on the outcome of recovery for stroke patients. "This tool can support the prediction of individual courses of recovery early on and will have an important impact on clinical management, translational research, and treatment choice," says Hummel.

(Boston)--High-risk neuroblastoma is an aggressive childhood cancer with poor treatment outcomes. Despite intensive chemotherapy and radiotherapy, less than 50 percent of these children survive for five years. While the genetics of human neuroblastoma have been extensively studied, actionable therapeutics are limited.

Now researchers in the Feng lab at Boston University School of Medicine (BUSM), in collaboration with scientists in the Simon lab at the Perelman School of Medicine at the University of Pennsylvania (Penn), have not only discovered why this cancer is so aggressive but also reveal a promising therapeutic approach to treat these patients. These findings appear online in the journal Cancer Research, a journal of the American Association for Cancer Research.

"Our work pinpoints a targeted therapy for treating this group of at-risk patients, likely leading to improved survival," said corresponding author Hui Feng, MD, PhD, associate professor of pharmacology and medicine at BUSM.

The research, led by Nicole M. Anderson, PhD, a former postdoc in the Feng lab and a current fellow in the Simon lab, combined patient sample analysis with genetic analysis of a zebrafish model of high-risk neuroblastoma and cell culture gene inactivation studies to understand the contribution of Dihydrolipoamide S-Succinyltransferase (DLST), a metabolic enzyme, and found that it promotes metastatic spread of this type of cancer.

"We show that elevated DLST expression not only predicts poor patient outcomes, but also disease aggression in human neuroblastoma. In the zebrafish model of neuroblastoma even a modest increase in DLST protein levels can accelerate neuroblastoma onset, increase tumor burden, and promote metastasis," explains Celeste Simon, PhD, co-corresponding author and scientific director and investigator at Abramson Family Cancer Research Institute, UPenn at Penn. Conversely, they found a 50 percent reduction in DLST impairs neuroblastoma initiation and suppresses tumor aggression. DLST depletion in human neuroblastoma cells decreases cell growth and induces apoptosis (cell death).

The researchers utilized cell lines together with zebrafish and mouse neuroblastoma models to test the therapeutic efficacy of IACS-010759, a drug that is in clinical trials for treating other cancers. "Our studies revealed that human neuroblastoma cells are sensitive to IACS treatment, which slowed tumor cell growth in all models tested," said Feng.

She hopes that this study will provide IACS-010759 as a targeted therapy for children with this aggressive disease.

Metastatic tumors originating from notoriously aggressive triple-negative breast cancer that emerge in the lungs contain a more diverse array of cancer cells than those that arise in the liver, according to a new study in mice and organs from deceased cancer patients. The study also identified a set of genes that distinguish lung and liver metastases; together, the findings may inform future research on how targeted therapies impact tumors across various microenvironments. While scientists have known that the presence of distinct tumor cell populations within the same tumor drives breast cancer progression, it has not been fully understood why this dangerous cellular diversity develops within some tumors and not others. To investigate how metastases vary based on host tissue type, Jean Berthelet and colleagues optimized a new optical barcoding strategy and analyzed 31 triple-negative breast cancer subclones (subpopulations of cells descended from cancer cells). The researchers injected fluorescently labeled cells into the mammary fat pads of mice with cancer and mapped the clonal composition of thousands of metastases in the lungs and liver, where triple-negative breast cancer cells tend to spread. They found that the inflammatory tumor necrosis factor alpha (TNF-? ) pathway was particularly upregulated in metastases in the lungs compared with those in the liver, with some genes in this pathway potentially responsible for the success of lung metastases. Berthelet et al. also collected 4 lung and 7 liver metastases from autopsies of 3 patients with breast cancer, confirming that the genes they identified were also expressed differently between the lungs and liver in humans.

Hamilton, ON (July 7, 2021) - A McMaster University team of researchers recently discovered how, exactly, the COVID-19 vaccines that use adenovirus vectors trigger a rare but sometimes fatal blood clotting reaction called vaccine-induced immune thrombotic thrombocytopenia or VITT.

The findings will put scientists on the path of finding a way to better diagnose and treat VITT, possibly prevent it and potentially make vaccines safer.

The researchers' article was fast-tracked for publication today by the prestigious journal Nature in its accelerated article preview because of the importance of the research.

"Our work also answers important questions about the connection between antibodies and clotting," said Ishac Nazy, principal investigator and corresponding author of the study. He added it will have both diagnostic and therapeutic implications.

Nazy is the scientific director of the McMaster Platelet Immunology Laboratory and an associate professor of medicine for the Michael G. DeGroote School of Medicine at McMaster.

The COVID-19 vaccines using adenoviral vectors, such as those from AstraZeneca and Johnson and Johnson, are associated with the VITT clotting disorder caused by unusual antibodies to blood platelets that are triggered by the vaccine.

The study shows, at a molecular level, how those unusual antibodies stick to components from blood platelets causing them to trigger clot formation.

"The antibodies stick to the platelet protein called platelet factor 4 (PF4) in a very unique and specific orientation, which allows them to align with other antibodies and platelets in the precise formation that leads to a self-perpetuating vicious cycle of clotting events," said Nazy.

"These disease-causing aggregates quickly activate platelets, creating a highly intense clotting environment in patients," he added.

The dangerous reaction to the adenovirus vector vaccines has been found to occur in one in 60,000 of people receiving the vaccine in Canada.

"The intention of our study was to better understand how the severe clots which characterize VITT develop," said Donald Arnold, study co-investigator and co-medical director of the McMaster Platelet Immunology Laboratory.

"A basic principle of medical care is to understand how the disorder happens and, in doing so, develop better treatments."

John Kelton, co-investigator of the study and co-medical director of the McMaster Platelet Immunology Laboratory, added: "We believe that this study is important because it clarifies how the clotting ensues, and because we have been able to identify the molecules involved.

"The next step is to develop a rapid diagnostic and accurate test to diagnose VITT. Our major interest is now to move upstream from how the clots happen to preventing them from occurring."

Current rapid tests yield false-negative results, and testing relies on more time-consuming tests to confirm VITT. This study now explains why the rapid tests frequently fail and allows for new strategies to improve diagnostic testing.

The investigators altered the molecular composition of the PF4 protein and, using this technology, were able to identify the binding region on the protein.

As society moves towards a renewable energy future, it's crucial that solar panels convert light into electricity as efficiently as possible. Some state-of-the-art solar cells are close to the theoretical maximum of efficiency--and physicists from the University of Utah and Helmholtz-Zentrum Berlin have figured out a way to make them even better.

In a new study, physicists used a technique known as cross-correlation noise spectroscopy to measure miniscule fluctuations in electrical current flowing between materials inside silicon solar cells. The researchers identified crucial electrical noise signals that are completely invisible to conventional noise-measuring methods. They were also able to pinpoint the likely physical processes causing the noise, which often results in a loss of energy and lower efficiency.

"Measuring noise on an object is relatively simple. You can just buy devices that do it. But the problem that plagues us is that these devices also have noise," said Kevin Davenport, associate instructor of physics at the U and lead author of the paper. "This cross-correlation technique allows us to not only measure the noise of the device, but to also measure the noise of our detector and remove it so that we can see much, much smaller noise signals."

The technique, that was published on June 24 in the journal Scientific Reports, is an important new tool to improve material interfaces for a better solar cell, or to analyze inefficiencies in other complicated devices.

"It's surprising how important tiny improvements in efficiency is for industry. Just a fraction of a percent improvement translates into billions of dollars because of the scale of production," said co-author Klaus Lips, professor of physics at Freie Universität Berlin and department head at Helmholtz-Zentrum Berlin where the solar cells have been designed and fabricated.

"In the past, we have used the cross-correlation technique to study fairly simple research-grade light emitting diodes, but advantages of the method truly came into the light in this work," said Andrey Rogachev, professor of physics at the U and co-author of the study. "And it goes beyond the solar industry. In any device with many layers, each interface between materials can diminish efficiency in some way. It's so complicated, you have to be really discreet to be able to say what's going on and, more importantly, where the particular noise is happening. It turns out that this technique allows us to do just that."

As often happens in modern research, a single method was not enough to understand complex devices. Interpretation of the noise date have been heavily helped by solar cell simulations carried out by C.T. Trinh, a postdoctoral researcher at Helmholtz-Zentrum Berlin and co-author of the study. The final co-author is Mark Hayward, then an undergraduate research at the U and now a graduate student at University of California, Irvine.

Analyzing noise

The study analyzed silicon heterojunction solar cells (HSCs), a high-end type of single-material solar cell and currently the most efficient of its kind on the market--26.7% of light that hits the cell is converted into electricity. In contrast, the cells that make up solar panels on a residential house range between 15% and 20% efficiency.

In an HSC, electricity generation starts when individual particles of light called photons are absorbed by the photo-active layer made of crystalline silicon and creates pairs of negatively charged electrons and positively charged holes, which are charges caused by missing electrons. Electrons and holes are then pulled in opposite directions by an electrical field created by two selective contacts made of hydrogenated amorphous silicon modified with impurities. This process produces current that we use as electricity. The problem is that the selective electrode and photo-active silicon do not match together perfectly, creating defects that trap electrons. To eliminate these defects in research-grade solar cells like the ones in the study, the scientists place between them an ultrathin layer of pure amorphous silicon. Finally, all of these five layers are sandwiched between two layers of transparent conducting material, known as ITO, and gold electrodes.

The efficiency of HSCs depends on how well the different layers are connected together. A slight mismatch between two layers can make it difficult for the electrons to get where they need to go--a problem that will produce a noise signal.

"That problem is kind of hidden inside these interfaces, and it's really difficult to be able to detect any kind of signal. But the noise technique that we use is very sensitive to really, really small individual signals," said Davenport. It's like listening to a note played by different instruments, he continued. A C-note on a violin is the same as a C-note on a cello, but they sound different. If you were to analyze that note, you can pull out information to learn something about the instrument that produced it, like the length or material of the strings.

"We do something similar to that. We see this wide spectrum of different noise signals and different positions along the frequency axis. We can say, 'OK, this part of the note that we see, we can attribute to this physical process and this part is a different physical process,'" said Davenport. "But the device is full of these processes that all generate noise and it's really difficult to un-entangle them--like pulling out a single voice in a 200-person chorus. This technique allows us to remove a lot of the unwanted portion of the signal."

Mapping inefficiencies

The silicon HSCs are excellent as they are, but they still have limits. The research team's new technique identified key areas in the device where specific physical processes are producing electrical signals. In the future, small adjustments at these stages could improve the efficiency of these cells, and solar cells of the future. After sifting through the electrical cacophony to discover the relevant signals, the physicists ran a simulation to pinpoint what physical processes were happening at the location of the signal.

The next generation of solar cells are known as tandem cells, which are stacks of different photovoltaic materials that are each sensitive to a different part of the sun's light, giving such a device an ability to generate more energy. One proposed device layer is the hot-ticket perovskite material.

"Together, the new solar cell can break through the limit of the silicon device by itself, beyond 30% efficiency," said Lips.

At this edge of efficiency, small losses matter. One such loss has been observed by material scientists; the deposition of the transparent ITO somehow modifies the underlying silicon layers, creating defects which reduce the device's efficiency. One of the major electrical noise signals that the researchers identified in this study was at this interface, where the charges are trapped and released. Another major signal occurred as holes passed through a similar barrier on the back side of the device.

"The ability to detect these signals means that we can understand their sources and mitigate them," said Davenport.

Dr Bock, under the mentorship of Distinguished Professor Dietmar Hutmacher, from QUT Centre for Biomedical Technologies, has focused her research on bone metastases from breast and prostate cancers.

She developed 3D miniature bone-like tissue models in which 3D printed biomimetic scaffolds are seeded with patient-derived bone cells and tumour cells to be used as clinical and preclinical drug testing tools.

The research team investigated their hypothesis that traditional anti-androgen therapy had limited effect in the microenvironment of prostate cancer bone tumours. The team's findings are published in Science Advances.

"We wanted to see if the therapy could be a contributor of cancer cells' adaptive responses that fuelled bone metastasis," Professor Hutmacher said.

"We developed an all-human, microtissue-engineered model of metastatic tissue using human bone-forming cells, prostate cancer cells and 3D printing."

Cancer biologist Distinguished Professor Judith Clements said the team bioengineered the microenvironment of a bone tumour to assess the effects of two clinically routinely used anti-androgen therapies - enzalutamide and bicalutamide - on the tumour cells.

"We found that the interactions between the cancer cells, the bone and the anti-androgens significantly impacted the progress of cancer in the mineralised microenvironment of bone tumours," Professor Clements said.

"This means that the efficacy of these therapies is compromised in the presence of the bone microenvironment."

Professor Hutmacher said an important outcome of the study was the need to upscale the bone tumour microenvironment model platform and make it available to other research groups.

"This would enable the prostate cancer research community to develop therapies for a more effective treatment of advanced prostate cancer."

In future, Dr Bock will use her model with patient-derived cells from patients undergoing prostatectomy, so that it could be used as a personalised preclinical diagnostic and drug testing tool.

"By screening existing and novel drugs using the bone tumour model in the laboratory, doctors will be able to treat individual patients with an anti-cancer therapy that can best suit their clinical need," Dr Bock said.

"This has the potential to considerably improve the quality of life of patients, because patients will not have to trial a succession of drugs, each of which carry the potential of severe side-effects, and which may not work for them."

This research was supported by the National Health & Medical Research Council of Australia, Australian Research Council and the Prostate Cancer Foundation of Australia.

Prostate Cancer Foundation of Australia CEO Professor Jeff Dunn AO said the findings were significant.

"This is an important discovery that will help us to better target treatments for men with different types of prostate cancer," he said.

"The findings also demonstrate the importance of ongoing research to improve our understanding of how different treatments impact disease progression and spread.

"Notably, Australia has one of the highest incidence rates of prostate cancer internationally, with 1 in every 6 Australian men likely to be diagnosed during their lifetime and around 17,000 men diagnosed each year.

"While survival rates for prostate cancer are high, with over 95% of men likely to survive at least five years, we must keep up the pace of work to find curative treatments, especially for advanced disease in the bone.

"There can be no doubt that this research will build on previous discoveries to help us save lives by stopping cancer from spreading and claiming the lives of more than 3,000 men a year, as is currently the case.

"We commend the research team and congratulate PCFA grant recipient Dr Nathalie Bock for her research achievements.

"This is Australian research excellence at its finest," he said.

QUT PhD researcher Zachariah Schuurs said the research team had identified a new binding site on the SARS-CoV-2 spike protein.

"Binding of the CoV-2 spike protein to heparan sulphate (HS) on cell surfaces is generally the first step in a cascade of interactions the virus needs to initiate an infection and enter the cell.

"Most research has focused on understanding how HS interacts on the receptor-binding domain (RBD) and furin cleavage site of the SARS-CoV-2 virus's spike protein, as these typically bind different types of drugs, vaccines and antibodies.

"We have identified a novel binding site on the N-terminal domain (NTD), a different area of the virus's spike that facilitates the binding of HS. This helps to better understand how the virus infects cells. The NTD is also a part of the spike protein that frequently mutates.

"Some antibodies in the blood that neutralise the viruses bind to the same region of the NTD.

"Therefore, targeting the NTD site with molecules like heparin (or heparin mimetics), a known anti-coagulant drug similar to HS, is a possible strategy to stop the virus binding to cells and infecting them."

Dr Neha Gandhi, from the QUT Centre for Genomics and Personalised Health, said COVID19 vaccines, although achieving success worldwide, were still far from being widely accessible.

"We need alternative antiviral strategies to prevent the spread of COVID-19 and treat infected people," Dr Gandhi said.

"Epidemiologists believe that persistent low-vaccine coverage in many countries will make it more likely for vaccine-resistant mutations to appear.

"Variants of concern have already emerged in South Africa, the US, India and Brazil. In this regard, alternate antiviral strategies are strongly needed to prevent the spread of COVID-19 and to treat people with COVID-19.

"Most SARS-CoV-2 variants have acquired a positively charged mutation in the spike protein. Molecules like heparin and its mimetics are negatively charged and therefore, these molecules could be used to treat people with severe effects of the virus and any emerging variants.

"Our research indicates that molecules that mimic the 3D structure of heparin with different sulphur chemistry, might be potential broad-spectrum antiviral drugs for COVID-19 and other emerging viral threats via direct interaction with the virus itself."

The multi-national study, "Evidence of a putative glycosaminoglycan binding site on the glycosylated SARS-CoV-2 spike protein N-terminal domain" published in the Computational and Structural Biotechnology Journal, used both computational and experimental techniques to confirm their finding.

The researchers used NCI Gadi and QUT Lyra supercomputers to model how HS and its inhibitor like heparin would interact with the spike protein.

Various researchers from the University of Queensland (Glycochemistry), Curtin University (Immunology), Zucero Pharmaceuticals and QUT conceptualised the study. These computational molecular simulations run by the QUT research team tested and confirmed the hypothesis that heparan sulphate could form a bridge between the newly identified binding site and another site on the spike important in the virus's infection.

A new study of lithium production in a classical nova found a production rate of only a couple of percent that seen in other examples. This shows that there is a large diversity within classical novae and implies that nova explosions alone cannot explain the amount of lithium seen in the current Universe. This is an important result for understanding both the explosion mechanism of classical novae and the overall chemical evolution of the Universe.

In the modern world, lithium is used in the rechargeable batteries powering smartphones and other devices. It was thought that most of the lithium found on Earth, and the rest of the Universe, was originally produced in classical nova explosions. Observations of the classical nova V339 Del using the Subaru Telescope supported this theory, providing the first observational evidence of large amounts of lithium being produced and ejected into space (Classical Nova Explosions are Major Lithium Factories in the Universe on February 18, 2015).

Now, a team led by Akira Arai, a researcher at Koyama Astronomical Observatory of Kyoto Sangyo University, used the Subaru Telescope's open-use observation program to study V5669 Sgr, a classical nova that appeared in Sagittarius in 2015. This was only the eighth time this type of study has been successfully conducted. Four of those eight, including the first, were conducted using the Subaru Telescope. This time is remarkable because the estimated lithium production is only a few percent of the production seen in the others. This indicates that there is a large diversity in novae. The fact that some novae produce only a small amount of lithium suggests that other objects, such as supernovae, may make important contributions to lithium production in the Universe.

Cheap to produce and long to degrade, plastic was once a manufacturing miracle. Now, plastic is an environmental plague, clogging landfills and choking waterways. A Japan-based research team has turned back to nature to develop an approach to degrading the stubborn substance. Similar to how a protein binds to cellulose in plants or to chitin in crustaceans to initiate decomposition, an engineered protein is on its way to binding to plastic particles in an effort to more efficiently break them down.

They published their results on June 29 in ACS Catalysis, a journal of the American Chemical Society.

"Polyethylene terephthalate (PET) is produced and used in large quantities in modern society due to its low cost and ease of processing," said paper author Ryota Iino, professor of the Institute for Molecular Science (IMS) in the National Institutes of Natural Sciences (NINS). "However, in recent years, from the perspective of realizing a sustainable society, the complete recycling of PET in industry and the removal of PET from the natural environment have become global issues. To resolve these issues, it is very important to understand how to degrade PET efficiently."

The researchers investigated and engineered an enzyme cloned from a library of genetic materials collected from nature. This enzyme -- called PET2 -- was found to facilitate the degradation of PET by accelerating the reaction between PET's chemical components and water.

Using single-molecule imaging analysis, the team found that the way the enzyme binds to the surface of PET actually limited the rate of degradation.

"We also revealed that by introducing positive charges on the surface of PET-degrading enzyme, the binding rate to the PET surface can be increased," Iino said.

The positive charges react favorably to the PET surface, so more of the enzyme can bind and more effectively degrade the PET. The researchers also found that while engineered PET2 showed high thermal stability and highest activity at 68 degrees Celsius -- slightly lower than most residential kitchen ovens can go -- it may be more effective at higher temperatures where PET's molecular bonds become more flexible and breakable.

"Our ultimate goal is to create a bacterium that can sense PET in the environment, move toward it, and degrade it," Iino said. Such a bacterium would then be able to turn the degraded PET into energy useful for other organisms, effectively acting as an automated recycling center for plastic. "In nature, chitin and cellulose are recycled in this way."

Iino is also affiliated with the School of Physical Sciences at The Graduate University for Advanced Studies (SOKENDAI). Other contributors include Akihiko Nakamura, Department of Applied Life Sciences, Faculty of Agriculture, Shizuoka University, and the Shizuoka Institute for the Study of Marine Biology and Chemistry; and Naoya Kobayashi and Nobuyasu Koga, Exploratory Research Center on Life and Living Systems (ExCELLS), NINS. Koga is also affiliated with IMS, NINS, and SOKENDAI.

The Leading Initiative for Excellent Young Researchers, the Ministry of Education, Culture, Sports, Science, and Technology of Japan, the Sumitomo Foundation, and the ExCELLS Special Collaboration Program supported this research.

In two recent articles published in Schizophrenia Bulletin, Sharon Hunter, PhD, an associate professor in the University of Colorado School of Medicine Department of Psychiatry, and M. Camille Hoffman, MD, MSc, an associate professor in the University of Colorado School of Medicine Department of Obstetrics and Gynecology, along with their research group, have uncovered a potential link between choline deficiency in Black pregnant women in the United States and increased risk of developmental and behavioral issues that can evolve into mental illness later in their children’s lives.

The first article, published in November 2020, is a study, titled, “Black American Maternal Prenatal Choline, Offspring Gestational Age at Birth, and Developmental Predisposition to Mental Illness.” The second, published last month and titled “Targeting Treatments to Health Disparities,” is a follow-up article delving more deeply into known healthcare disparities highlighted by the study results.

The studies are the result of more than 20 years of research by the group, which began with a general goal of understanding in utero risk factors of schizophrenia.

“At that time, there was a lot of discussion around the idea that mental illnesses like schizophrenia were tied to prenatal neurodevelopment,” Hunter says.

Early choline clinical trial

Choline is an essential nutrient that can be found in foods such as milk, red meats, and eggs. Based on previous studies of choline showing that it is vital for fetal neurodevelopment, including the development of inhibitory neurocircuits in the brain that are abnormal in individuals with schizophrenia and many of their family members, the group launched its first clinical trial in 2004. During the trial, they supplemented pregnant women with a specific form of choline called phosphatidylcholine, then monitored their children until the age of four. Phosphatidylcholine is less likely to cause side effects, such as stomach upset, associated with pure choline. The results of the trial showed that those inhibitory neurocircuits were functioning properly in more children from supplemented moms than in children whose mothers didn’t receive the supplement.

“It showed that mothers who had lower choline levels during the second trimester of pregnancy gave birth to babies who were more likely to have worse neurodevelopmental scores, which can be a marker for later mental illness or behavioral problems,” Hoffman says.

The ultimate goal was to uncover whether supplementing with choline could help prevent schizophrenia, but since the condition isn’t typically diagnosed until a patient is in their 20s, the group instead monitored for the some of the disease’s early indicators.

“We couldn’t follow these children for 20 years, but we could test them as children to see if they had problems with attention or withdrawal or aggression, which can be indicators not just of schizophrenia but of other mental issues as well,” Hunter explains.

Uncovering a racial health care disparity

After the first choline trial, the group conducted a follow-up study in which they measured choline levels in 183 pregnant women. Although the women were told about choline and the researchers suggested that they try to get more choline in their diets, they did not administer any choline supplements to the participants. It was during this study that the group noticed a demographic disparity: overall, choline levels were markedly lower in Black women than any other group.

“When we found these differences in choline levels, we started to wonder whether this also translated to differences in outcomes,” Hunter says. “And preliminary data suggests that it does.”

This disparity in choline levels prompted the researchers to look back at the results of the first clinical trial. When they did, they found that the gestational age at delivery in Black mothers who had been supplemented with choline was extended by an average of three weeks compared to Black mothers who didn’t receive supplementation.

“As an Ob/Gyn, preterm birth is one of the main adverse pregnancy outcomes that we're always working towards preventing,” Hoffman says. “And there are known disparities in both birth weight and risk of preterm birth between Black women and their children and almost every other group.”

Since preterm birth can have adverse effects on the development of cognition and behavior throughout childhood — including mental health — the results of the clinical trial and the subsequent observational study seem to point to two potential benefits of choline supplementation for pregnant women, and, in particular, Black women: enhanced prenatal development of inhibitory neuro-circuits in the brain and older gestational age at delivery.

How systemic racism in the U.S. may play a role in stress and pregnancy

Now the researchers were faced with the question of why Black mothers’ choline levels were so much lower than those of other women? They compared the choline levels of the Black pregnant women in the American study to blood samples from a cohort of pregnant women in Uganda and found that the choline levels of the Ugandan women were much higher than their American counterparts.

“Of course, we know that not all Black women in America are African American or of African heritage, Hunter says. “But still, it seemed like there was something else going on that might account for the racial differences we were seeing.”

So, they turned their attention to a potential culprit and differentiator: stress.

“Part of my contribution to the research group early on was looking at ways to capture and measure stress in relation to two primary pregnancy outcomes,” Hoffman says. “One was gestational age at birth and the other was birth weight, because both of those are markers for either long-term wellness or potential impairments.”

One of the group’s hypotheses was that the more stressed a mother is, the more her liver may sequester choline for itself, meaning that the fetus may not receive an adequate amount for neurodevelopment and is more at risk for preterm birth.

The team used Hoffman’s methods to collect measures of maternal stress in the observational study participants. And while the Black women didn't report feeling more stress, their hair cortisol levels, a biomarker of stress exposure, were higher than those of participants of other races.

“Even though they don't report it, their bodies looked more stressed,” Hunter says. “Our question now is whether there are stressors that Black women experience but that our questionnaires do not capture, or are cortisol levels reflecting accumulated exposure to low-level, background stressors, perhaps stemming from decades or lifetimes or even generations of institutional racism in this country. We don’t have the data to answer those questions yet, but we wanted to get this study out there to say, ‘this is something we should be paying attention to.’”

Could choline be the next folic acid?

The Food and Drug Administration (FDA) currently recommends that pregnant women get 550 milligrams of choline a day, but Hunter says that about 90% of pregnant women don't meet that goal.

“That's hard to do,” she says. “It's not that it can't be done, but it would be difficult. There have also studies that tried to raise choline levels in women by bringing them into a laboratory and providing them with high-choline foods, but they were not very successful.”

“The same was true for folic acid studies 20 years ago,” says Hoffman. “We recommend folic acid for pregnant women because it has a major impact on reducing neural tube defects. But the same story played out back in the early days of folic acid research, where the risk was significantly reduced when folate was included in a supplement versus trying to get people achieve adequate dietary intake. Dietary changes are hard to make, but we know you're going to get higher choline levels when you supplement.”

Hunter says the group hopes to do another clinical trial in the future where they supplement one cohort of Black women at the FDA-recommended choline level, plus another group at about two to three times the recommended amount to see if there is any additional benefit to supplementing at a higher level.

“If we're telling women that they need 550 milligrams of choline per day, but some other factor limits how much choline can get to the fetus, that level of intake may not adequately meet the needs of the developing fetus. We need to understand this,” she says.

Unfortunately, the supplements can be expensive: usually $600–$800 over the course of a pregnancy, and up to about $1,200 for some of the more expensive supplements.

Both Hoffman and Hunter hope to continue to raise awareness around this issue and the health disparity when it comes to Black women.

“For over 50 years, maternal fetal medicine has been trying to figure out ways that we can reduce preterm birth, and then we find a promising contender in the choline data set,” Hoffman says. “It's especially exciting because a major push in obstetrics right now is trying to close these known gaps in outcomes that exist for Black women and their children. The choline and cortisol connection gives us objective, physiologic measures to sort out what changes we need to make in terms of addressing health disparities”

Journal

Schizophrenia Bulletin

DOI

10.1093/schbul/sbab051

Australian scientists researching how our immune system responds to COVID-19 have revealed that those infected by early variants in 2020 produced sustained antibodies, however, these antibodies are not as effective against contemporary variants of the virus.

The research is one of the world's most comprehensive studies of the immune response against COVID-19 infection. It suggests vaccination is more effective than the body's natural immune response following infection and shows the need to invest in new vaccine designs to keep pace with emerging COVID variants.

Published today in PLOS Medicine, the study was made possible by a partnership between the University of Sydney, Kids Research, Sydney Children's Hospitals Network, the Kirby Institute at UNSW Sydney, Australian Red Cross Lifeblood, St Vincent's Hospital and NSW Health Pathology, as well as other local and international collaborators.

The team analysed the serum of 233 individuals diagnosed with COVID-19 over 7 months and uncovered that the level of immunity over time is dependent on disease severity and the viral variant. They show that antibodies developed during the first wave had reduced effectiveness against six variants, ranging from those observed in the second wave in Australia through to three variants of concern that have driven the global pandemic in the UK, Brazil and South Africa.

How do we study the immune response?

The serum of COVID-19 infected individuals was of interest as it is the part of our blood that contains crucial information about our immune system. Analysis of the serum made it possible to create a detailed timeline of the level of 'neutralising antibodies' produced against COVID-19 infection, and so to see if there was long-term immunity.

Neutralising antibodies are part of our immune system's frontline arsenal that is triggered during infection and vaccination. Their job is to shield cells that are usually the target of a pathogen (such as the SARS-CoV-2 virus which causes the COVID-19 disease) from being infected. The level of neutralising antibody response can be a defining feature of how effectively our body fights off illness.

Interestingly, a rare group of 'super responders' was also identified as an exception.

This group of 'super responders' had a stable and robust level of antibodies across all COVID-19 variants. The researchers say this group could prove useful for investigating the potential of convalescent plasma (using blood from people who have recovered to treat others) which has so far proven ineffective against severe COVID-19 illness. In addition, key donors could be looked at closely and their antibodies cloned for future therapeutic use.

Why it is important?

Co-senior author Associate Professor Fabienne Brilot of the University of Sydney and Kids Research, Sydney Children's Hospitals Network, and her research team led the analysis branch of the study, using highly sensitive tools they developed to study the antibodies in detail.

"We can learn a great deal from these people who were infected in the first wave in Australia as they were infected with the same variant that our current vaccines are based on," said Associate Professor Brilot.

"While the approved vaccines are showing good responses, our study highlights the importance of continued vaccine development, especially taking into account the differences in variants."

Co-senior author Associate Professor Stuart Turville of the Kirby Institute said the study was conducted to investigate the level, breadth and longevity of the immunity generated from COVID-19 infection and whether mutation of the virus compromises immunity.

"What this work has shown us is that current observations about vaccines show they offer a much broader protection against COVID-19 and its variants than the body's natural immune response following infection, which is usually only protective against the variant of the virus that the person was infected with. We, therefore, should not rely on the body's natural immune response to control this pandemic, but rather the broadly protective vaccines that are available."

Key findings

SARS-CoV-2 antibody responses are sustained for up to seven months post-infection.

The immune response remained stable in some individuals, and while it decreased in others, no individual showed a negative response during the seven-month period.

Levels of virus-neutralising antibodies were associated with COVID-19 severity.

Antibodies generated after early infection displayed a significantly reduced antibody binding and neutralisation potency to globally emerging viral variants.

Methods

The study analysed the serum from 233 individuals who were diagnosed with COVID-19 from February to October 2020. There were two cohorts to the study--a hospital-based cohort of patients (the ADAPT study at St Vincent's Hospital, Sydney) recruited during the first and second wave of infection in Australia and a national cohort of plasma donors (LIFEBLOOD).

10 COVID-19 strains and variants of concern/ interest were investigated, including:*

First known classified SARS-CoV-2 strain (Wuhan -1 D614)

Alpha (B.1.1.7, United Kingdom)

Beta (B.1.351, South Africa)

Gamma (P1, Brazilian)

Zeta (P2, Brazilian)

*Note naming conventions updated to reflect World Health Organisation classifications

The researchers used a comprehensive suite of assays that measured:

The longevity and type of antibody response against Spike from various variants over time in serum of COVID-19 diagnosed individuals.

Neutralisation of infectious SARS-CoV-2 over time, by infecting cell lines that had ACE2 on its surface (which SARS-CoV-2 binds and targets on the cell to begin infection) with a particle designed to mimic a version of the SARS-CoV-2 virus particle.

Polymer composite materials that combine magnetic and electrical properties are the subjects of particular attention for modern-day researchers. Their basic property is the ability to convert electric polarization into a magnetic field and vice versa. Although some materials exhibit a much better magnetoelectric effect, polymer-based composites are easier not only to produce but also to modify.

Such composites have great potential in a variety of different fields. For example, using them as a basis, scientists can develop surfaces that help cultivate various cells. In this case, polymer composites serve as a substrate through which it is possible to affect the culture using a non-contact and controlled electric charge and morphological properties of the surface. It allows simulating natural conditions in the body. Due to such ample opportunities, researchers have been trying to improve the efficiency of the material for several years.

With the help of Russian and foreign colleagues, scientists from the I. Kant Baltic Federal University created two types of composites based on poly(vinylidene fluoride) (PVDF) polymers and a PVDF-based copolymer with the use of PVDF-TrFE trifluoroethylene.

Poly(vinylidene fluoride) is a multipurpose material with a wide array of applications. In a certain crystalline phase, it possesses piezoelectric properties that are expressed in the emergence of electrical polarization under the mechanical influence. Composites developed by the researchers demonstrate a change in polarization both under mechanical impact and the influence of a magnetic field due to the inclusion of magnetic nanoparticles in the polymer structure.

The researchers followed various approaches to modify nanocomposites in order to amplify and control the magnetoelectric response. They used a PVDF-based copolymer with extra pronounced piezoelectric properties, then tried additives from piezoelectric and magnetic particles. The results of the experiments show that the addition of particles of barium titanate (BaTiO3) with a concentration of 5-10% can significantly enhance the magneto-electric effect.

"We have also shown that our composites are biocompatible, that is, they do not harm living systems. This was confirmed in our experiment with the embryonic stem cells of mice. This type of cell is very sensitive to the conditions of cultivation, including the properties of the substrate. Further research will be aimed at increasing the magnetoelectric effect. This is possible due to changes in the size, shape, and concentration of particles in such composites", Kateryna Levada comments, Ph.D., the Head of the Biomedical Applications Laboratory of the REC "Smart Materials and Biomedical Applications".

DANVILLE, Pa. - Having multiple chronic health conditions and living in a rural area were the top two factors affecting increased healthcare system contact among older patients with bladder cancer, a research team has found.

The Geisinger-led team evaluated 73,395 Medicare beneficiaries age 66 and older who had been diagnosed with non-muscle-invasive bladder cancer to assess their treatment burden, defined as the number of days the patients had contact with a health system in the year following diagnosis.

Nearly two-thirds of the patients had multiple co-existing chronic conditions at the time of bladder cancer diagnosis, as well as other aging-related conditions, including a history of falls, cognitive impairment, depression, weight loss or urinary incontinence. The mean treatment burden for the group was 8.9 days.

The research team found that the presence of multiple co-existing conditions had the largest effect on treatment burden, with each additional condition increasing the average number of health system contact days by 13%. Regardless of the number of chronic conditions reported, rural patients consistently had higher treatment burden than their urban counterparts.

The results were published in the Journal of Geriatric Oncology.

"These findings highlight the need for interventions that reduce treatment burden among the growing population of older adults with cancer, particularly in rural areas," said Tullika Garg, M.D., M.P.H., a urologic oncologist at Geisinger and lead author of the study. "Cancer care, and care for other chronic conditions, goes beyond a single-disease approach and needs to account for the whole person."

Geisinger is making better health easier for patients age 65 and older and those with chronic conditions through innovative programs like 65 Forward Health Centers, offering personalized primary care and wellness services for Geisinger Gold members, and Geisinger at Home, bringing care into the home for Geisinger Gold members with certain chronic conditions.

Researchers from IDIBELL and the University of Barcelona (UB) have described that neurons derived from Parkinson's patients show impairments in their transmission before neurodegeneration.
For this study, it has been used dopaminergic neurons differentiated from patient stem cells as a model.

Parkinson's is a neurodegenerative disease characterized by the death of dopaminergic neurons. This neuronal death leads to a series of motor manifestations characteristic of the disease, such as tremors, rigidity, slowness of movement, or postural instability. In most cases, the cause of the disease is unknown, however, mutations in the LRRK2 gene are responsible for 5% of cases.

Current therapies against Parkinson's are focus on alleviating the symptoms but do not stop its progression. It is thought that early interventions before the appearance of the first symptoms that prevent neuronal death could slow down or even stop the evolution of the disease. However, currently, the diagnosis is based on the appearance of symptoms, when 70% of the neurons have already been lost.

A group of researchers from IDIBELL and the University of Barcelona (UB), led by Dr. Antonella Consiglio (group leader at IDIBELL, ICREA Academy researcher, and professor at the Faculty of Medicine and Health Sciences of the UB and IBUB/Institute of Biomedicine of the UB), Dr. Angel Raya (coordinator of the IDIBELL Regenerative Medicine program and ICREA researcher) and Dr. Jordi Soriano (group leader and professor at the UB and the Institute of Complex Systems from the University of Barcelona), with other national and international collaborators, have identified early functional deficiencies, before death, in neurons derived from patients with genetic Parkinson's. According to Dr. Consiglio ", these discoveries open the door to early diagnosis, which would allow us to carry out a premature intervention that would slow down neuronal death, and therefore, would stop the evolution of the disease".

In this work, dopaminergic neurons, the most vulnerable in Parkinson's, differentiated from stem cells (iPSC) of healthy individuals and patients with genetic Parkinson's, have been used as a model. Researchers have observed that these dopaminergic neurons are capable of maturing and forming functional neural networks in culture, in both control and Parkinson's disease conditions.

However, in this work published in npj Parkinson's Disease, it is shown that neurons from individuals with Parkinson's are more spontaneously active and present more explosion episodes in which, for example, the entire network is activated at the same time. All this before the neurodegeneration. The researchers believe that this early neuronal dysfunction could be contributing to initiating the cascade of events responsible for the death of dopaminergic neurons, and consequently, Parkinson's disease. Furthermore, this work highlights the extraordinary window of opportunity provided by experimental models based on iPSC in the understanding and presymptomatic evaluation of neurodegenerative diseases.

This work was supported by the European Research Council-ERC, the Spanish Ministry of Economy and Competitiveness, the Carlos III Institute, AGAUR, and the CERCA program of the Generalitat de Catalunya.

By combining two distinct approaches into an integrated workflow, Singapore University of Technology and Design (SUTD) researchers have developed a novel automated process for designing and fabricating customised soft robots. Their method, published in Advanced Materials Technologies, can be applied to other kinds of soft robots--allowing their mechanical properties to be tailored in an accessible manner.

Though robots are often depicted as stiff, metallic structures, an emerging class of pliable machines known as soft robots is rapidly gaining traction. Inspired by the flexible forms of living organisms, soft robots have wide applications in sensing, movement, object grasping and manipulation, among others. Yet, such robots are still mostly fabricated through manual casting techniques--limiting the complexity and geometries that can be achieved.

"Most fabrication approaches are predominantly manual due to a lack of standard tools," said SUTD Assistant Professor Pablo Valdivia y Alvarado, who led the study. "But 3D printing or additive manufacturing is slowly coming into play as it facilitates repeatability and allows more complex designs--improving quality and performance."

According to Dr Valdivia y Alvarado, embedded 3D printing--wherein various material inks are extruded in a supportive matrix--is especially suited for fabricating soft robots made of multiple materials or composites. However, to ensure that these robots are optimally designed, the team turned to topology optimisation (TO), where mathematical models are employed to design bespoke structures within a set of constraints.

By automating these two key steps in a single framework, the authors hoped to develop an integrated workflow for creating customised soft robots and minimise potential errors along the way. For the study, the group used a swimming autonomous robot inspired by batoids. The workflow starts by defining the robot's fin geometry, after which TO is used to generate the desired structure with desired properties within prescribed material and motion constraints. The optimised design is then transformed into a code that is read by the team's custom-built 3D printers, which in turn fabricate the robot.

The batoid-inspired soft robots were designed to survive the marine environment's harsh conditions and the approach focused on tailoring their fin composition and assessing how these changes could impact the fabricated robot's swimming performance.

Specifically, three types of fins were created--with two fins respectively made of soft and stiff materials as well as a third fin designed through TO combining the two materials. Unlike the first two fins, which were fabricated using traditional methods, the third composite fin was made following the integrated workflow.

Incredibly, the soft robot with the optimised composite fins was 50 per cent faster than its counterpart with the traditionally casted soft fin, with a speed slightly higher than the robot with the hard fin. The same prototype with the composite fin also turned roughly 30 per cent faster compared to the soft fin and had the smallest turning radius among the three robots--making it better at maneuvering through water.

Having successfully demonstrated the effectiveness of their approach, Dr Valdivia y Alvarado noted that their workflow for fabricating optimised, multi-material soft robots can be universally applied to design other soft robots.

"For example, if we're building a sensor, our objective in TO could be to tailor the electrical conductivity of certain portions of the structure," said Dr Valdivia y Alvarado. "Customising optical, thermal, electrical, as well as other physico-chemical properties would also be interesting for other applications."