While there is substantial research into developing interventions to repair injured tissue, scientists at Washington University School of Medicine in St. Louis focused instead on developing, in mice, an immunotherapy to minimize the damage from traumatic spinal cord injury. Their findings show that immunotherapy can lessen such damage by protecting neurons at the injury site from being attacked by immune cells.

The study, published Sept. 4 in Nature, demonstrates success in mice given the immunotherapy and presents a novel approach with potential to help improve outcomes for people recovering from spinal cord injuries.

“Immune cells in the central nervous system have a reputation for being the bad guys that can harm the brain and spinal cord,” said senior author Jonathan Kipnis, PhD, the Alan A. and Edith L. Wolff Distinguished Professor of Pathology & Immunology and a BJC Investigator at WashU Medicine. “But our study shows that it’s possible to take advantage of immune cells’ neuroprotective function, while controlling their inherent detrimental abilities, to help in the recovery from central nervous system injury.”

Shortly after injury to the nervous system, immune cells flood the site. Among them is a mixture of activated T cells — a subset of immune cells — that either harm or protect the surrounding neurons. Wenqing Gao, PhD, a postdoctoral research associate in the Department of Pathology & Immunology and the study’s first author, analyzed T cells from the spinal cords of injured mice and performed a genetic analysis to decode their identities. Her goal was to separate the harmful from the protective T cells and create numerous copies of the beneficial cells with which to treat the injured mice.

But there was a catch, she found. The protective T cells that swoop into the injury site can mistakenly attack the body’s surrounding tissues when activated for too long, causing autoimmune disease. To improve the therapy’s safety, Gao modified the cells to shut off after a few days.

Mice given the modified T cells had better mobility than did the untreated mice. The researchers saw the biggest improvements when the mice were infused with T cells within a week of the injury. None of the mice receiving immunotherapy developed a destructive autoimmune reaction.

“There are no effective treatments for traumatic injuries to the central nervous system,” explained Gao. “We developed immunotherapy for such injuries by taking advantage of the protective immune cells that infiltrate the injury site and found that it dramatically improved mobility in mice.”

In collaboration with WashU Medicine’s Wilson Zachary Ray, MD, a spinal cord surgeon and the Henry G. & Edith R. Schwartz Professor of Neurosurgery, the researchers also looked every day for a week for T cells in the cerebral spinal fluid of patients with spinal cord injuries. They found a significant expansion of the T cells, confirming the feasibility of expanding protective T cells from such patients to generate the immunotherapy.

“Our future goal is to devise a clinical trial to test the therapy in people with such injuries, while expanding this work to neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) as well as Alzheimer’s and Parkinson’s diseases,” Gao said.

Added Kipnis: “Although the initial trigger in neurodegenerative diseases is different, the subsequent death of neurons may very well be mediated by similar processes, opening an opportunity for adapting our engineered cells for use as a therapy in neurodegeneration.”

This work was supported by the BJC Investigators Program at WashU.

A new study from MIT offers an explanation for how collagen can survive for so much longer than expected. The research team found that a special atomic-level interaction defends collagen from attack by water molecules. This barricade prevents water from breaking the peptide bonds through a process called hydrolysis.

“We provide evidence that that interaction prevents water from attacking the peptide bonds and cleaving them. That just flies in the face of what happens with a normal peptide bond, which has a half-life of only 500 years,” says Ron Raines, the Firmenich Professor of Chemistry at MIT.

Raines is the senior author of the new study, which will appear in ACS Central Science. MIT postdoc Jinyi Yang PhD ’24 is the lead author of the paper. MIT postdoc Volga Kojasoy and graduate student Gerard Porter are also authors of the study.

Water-resistant

Collagen is the most abundant protein in animals, and it is found in not only bones but also skin, muscles, and ligaments. It’s made from long strands of protein that intertwine to form a tough triple helix.

“Collagen is the scaffold that holds us together,” Raines says. “What makes the collagen protein so stable, and such a good choice for this scaffold, is that unlike most proteins, it’s fibrous.”

In the past decade, paleobiologists have found evidence of collagen preserved in dinosaur fossils, including an 80-million-year-old Tyrannosaurus rex fossil, and a sauropodomorph fossil that is nearly 200 million years old.

Over the past 25 years, Raines’ lab has been studying collagen and how its structure enables its function. In the new study, they revealed why the peptide bonds that hold collagen together are so resistant to being broken down by water.

Peptide bonds are formed between a carbon atom from one amino acid and a nitrogen atom of the adjacent amino acid. The carbon atom also forms a double bond with an oxygen atom, forming a molecular structure called a carbonyl group. This carbonyl oxygen has a pair of electrons that don’t form bonds with any other atoms. Those electrons, the researchers found, can be shared with the carbonyl group of a neighboring peptide bond.

Because this pair of electrons is being inserted into those peptide bonds, water molecules can’t also get into the structure to disrupt the bond.

To demonstrate this, Raines and his colleagues created two interconverting mimics of collagen — the one that usually forms a triple helix, which is known as trans, and another in which the angles of the peptide bonds are rotated into a different form, known as cis. They found that the trans form of collagen did not allow water to attack and hydrolyze the bond. In the cis form, water got in and the bonds were broken.

“A peptide bond is either cis or trans, and we can change the cis to trans ratio. By doing that, we can mimic the natural state of collagen or create an unprotected peptide bond. And we saw that when it was unprotected, it was not long for the world,” Raines says.

“No weak link”

This sharing of electrons has also been seen in protein structures known as alpha helices, which are found in many proteins. These helices may also be protected from water, but the helices are always connected by protein sequences that are more exposed, which are still susceptible to hydrolysis.

“Collagen is all triple helices, from one end to the other,” Raines says. “There’s no weak link, and that’s why I think it has survived.”

Previously, some scientists have suggested other explanations for why collagen might be preserved for millions of years, including the possibility that the bones were so dehydrated that no water could reach the peptide bonds.

“I can’t discount the contributions from other factors, but 200 million years is a long time, and I think you need something at the molecular level, at the atomic level in order to explain it,” Raines says.

The research was funded by the National Institutes of Health and the National Science Foundation.

Many different types of cells work together in the brain. In humans, nerve cells (neurons) make up less than half of the cells. The rest are called “glia.” The most common glial cells are astrocytes. They supply the neurons with nutrients, form part of the blood-brain barrier, regulate the synapses and support the immune cells.

However, a small proportion of astrocytes are able to produce nerve cells and other types of brain cells. These special astrocytes are therefore also known as brain stem cells. Brain stem cells and ordinary astrocytes hardly differ in their gene expression, i.e. in the activity of their genes. “How they can perform such different functions and what makes up the stem cell properties was previously completely unclear,” explains Ana Martin-Villalba, stem cell researcher at the DKFZ.

Methylation is the key

To solve this puzzle, the teams led by Martin-Villalba and Simon Anders (University of Heidelberg) isolated both ordinary astrocytes and brain stem cells from one of the regions of the brain where young neurons still develop in adult mice, the “ventricular-subventricular zone” (vSVZ). The researchers analyzed gene expression at the level of individual cells using mRNA sequencing as well as the patterns of methylation (“methylome”) in the entire genome. They used a specially developed tool to analyze the methylation data*.

DNA methylation refers to chemical “markers” with which the cell can switch off unused parts of its DNA. Methylation is therefore crucial for the identity of the cells.

During this study, the stem cell experts noticed that brain stem cells have a special DNA methylation pattern that distinguishes them from other astrocytes. “Unlike normal astrocytes, certain genes are demethylated in brain stem cells that are otherwise only used by nerve precursor cells. This allows the brain stem cells to activate these genes in order to produce nerve cells themselves,” explains Lukas Kremer, first author of the current publication. Co-first author Santiago Cerrizuela adds: “This pathway is denied to ordinary astrocytes, as the required genes are blocked by DNA methylation.”

Lack of blood supply triggers reprogramming of astrocytes to stem cells and increases new nerve formation

Could methylation also be used to convert astrocytes into brain stem cells in other regions of the brain, outside the vSVZ? “This would be an important step for regenerative medicine to repair damaged areas of the brain,” says Ana Martin-Villalba.

Earlier studies had already shown that a lack of blood supply, such as occurs in brain injuries or stroke, increases the number of newborn nerve cells. Do altered methylation profiles play a role in this process?

To investigate this, the researchers interrupted the blood supply to the brain of mice for a short time. As a result, astrocytes with the typical stem cell methylation profile could be detected even outside the vSVZ, as well as an increased number of nerve progenitor cells.

“Our theory is that normal astrocytes in the healthy brain do not form nerve cells because their methylation pattern prevents them from doing so,” explains study head Martin-Villalba. “Techniques to specifically alter the methylation profile could represent a new therapeutic approach to generate new neurons and treat nerve diseases.”

“The lack of blood supply apparently causes astrocytes in certain areas of the brain to redistribute the methyl marks on their DNA in such a way that their stem cell program becomes accessible. The reprogrammed cells then begin to divide and form precursors for new neurons,” summarizes Simon Anders and adds: “If we understand these processes better, we may be able to specifically stimulate the formation of new neurons in the future. For example, after a stroke, we could strengthen the brain’s self-healing powers, so that the damage can be repaired.”

Why studies on mice are necessary for this research

Strokes or accidents can lead to damage to the brain that is generally irreparable at present and often has dramatic consequences for those affected. As of today, there is no way to replace lost nerve cells. The aim of this work is to find ways to stimulate the regeneration of nerves in the adult brain.

This requires a profound understanding of how and under what circumstances brain stem cells can be induced to provide a supply of young nerve cells. To do this, the researchers need to study developmental processes that only take place in the brains of highly developed mammals. Epigenetic reprogramming cannot be observed in living animals using imaging techniques, but requires studies at the level of individual cells. The investigations cannot be carried out on cells from the culture dish, as the methylation profile of the astrocytes changes as soon as they are taken into culture, so that the epigenetic reprogramming can no longer be traced.

Researchers have warned that the current system is failing many young adults as they transition from children’s to adult’s services — suddenly finding themselves unable to access treatment because services do not link up effectively.

More than 750 people from across the country — including commissioners, healthcare professionals working in primary care, and people with lived experience of ADHD — completed the MAP National Survey, which highlights challenges that GPs face when prescribing ADHD medication.

ADHD affects up to seven per cent of children and up to five per cent of adults, with symptoms including patterns of hyperactivity, impulsivity and/or inattention which interfere with functioning in daily life. Failure to treat ADHD and gaps in treatment, especially as young people become adults, can have severe impacts for patients and families, increasing the risk of mental health crises and difficulties with work, education, and relationships. This failure also places additional pressure on those working in health services.

The survey found variations in “shared care” agreements between GPs, mental health specialists and patients — which need to be in place for GPs to be able to prescribe ADHD medications. This was a particular problem when young people move to adult mental health services, suggesting the current system lets down adolescents at a critical time in their lives. Current NICE guidelines recommend GPs prescribe medication for adult ADHD patients under a shared care agreement with adult mental health services.

However, the survey found that such agreements are not always easy to set up, with evidence suggesting that GPs may not feel sufficiently supported to prescribe in this way. Indeed, if appropriate support is not in place, some GPs may not prescribe ADHD medication due to concerns around insurance and liability. This can be a particular problem for patients with a private diagnosis of ADHD, and leaves GPs unable to provide effective care, and many patients without access to the medication they need.

Furthermore, more than 40 per cent of survey respondents reported waiting times of two years or more for an appointment with adult mental health services. This leaves GPs with the responsibility for providing care, but without the support they need to offer the best care for their patients at a crucial time in their lives. This can include removing access to medication, despite the treatment having been successful during childhood. Issues with access to treatment for ADHD are also worst for some underserved groups, such as young women, and young people leaving care, which is increasing health inequalities.

The survey results come just as NHS England has announced the establishment of a taskforce and a major review of ADHD services. As stated by NHS England: “People with ADHD deserve a caring and effective service from the NHS and wider society. We know there is more to do, but we do not underestimate the complexity and challenges in realising this ambition.”

Dr Anna Price, Senior Research Fellow at the University of Exeter, said: “Our findings highlight the need for a coordinated approach to address problems that lead to a postcode lottery for patients trying to access treatment for ADHD. GPs and other primary care professionals really need better support so that they can provide shared care prescribing of ADHD medication in line with UK guidelines.

“We know that failing to treat ADHD can have a huge impact. Turning 18 is often a crucial and sensitive time in life, and our research shows that lack of treatment at this time can be particularly damaging for young people who are learning to self-manage their health needs, at the same time as perhaps sitting important exams, leaving home for the first time, and embarking on careers or university study.

“We welcome the establishment of the NHS England taskforce and is a much-needed step towards better outcomes for people with ADHD.”

University of Exeter experts have recently established a Science of ADHD and Neurodevelopment collaboration, working together with people who are experts by experience, and healthcare providers. The collaboration aims to develop solutions, such as curated digital interventions and standardised shared care agreement templates, to help people with ADHD to thrive.

The study found that Global South cities have just 70% of the “cooling capacity” provided by urban greenery in the Global North.

With temperatures rising, combined with the “urban heat island” effects that make cities hotter than rural areas, heat-related illness and death in cities are becoming more common.

Urban green spaces can help reduce this risk, cooling down outdoor environments and providing vital refuges.

The research — led by an international team including Nanjing, Exeter, Aarhus and North Carolina State universities — finds there is “vast potential” to enhance urban cooling in the Global South and reduce inequality.

“Urban greenery is a really effective way of tackling what can be fatal effects of extreme heat and humidity,” said Professor Tim Lenton, of the Global Systems Institute at the University of Exeter.

“Currently, the people dying due to climate change are often in the slums of cities in the Global South, such as the hottest parts of India.

“Our analysis suggests green spaces can cool the surface temperature in the average city by about 3°C during warm seasons — a vital difference during extreme heat.”

The cooling effect of urban green spaces, especially urban forests, is caused by shading and transpirational cooling (evaporation of water).

The new study used satellite data on the world’s 500 largest cities to assess “cooling capacity” — the extent to which urban green spaces cool down a city’s surface temperatures.

All of the top ten cities for cooling capacity are in the USA: with Charlotte and Raleigh-Durham first, followed by Kansas and Baltimore. Many US cities have low population density — leading to issues of urban “sprawl” — but this brings benefits in terms of green spaces and resulting cooling.

Mogadishu in Somalia is the city with the lowest cooling capacity, followed by Sana’a in Yemen and Rosario in Argentina. Chicago is fourth-lowest — the only US city on the list with cooling capacity below 1°C.

‘Cooling benefit’

The Global South — which includes Africa, Latin America and much of Asia — contains the areas most at risk from extreme heat.

A previous study found that current climate policies will leave more than a fifth of humanity exposed to dangerously hot temperatures by 2100, with the largest at-risk populations in India and Nigeria.

The new study assessed population density and location to estimate the “cooling benefit” received by the average citizen — as green areas are often found in the richer parts of a city.

Professor Chi Xu, of Nanjing University, said: “As well as Global South cities lagging behind in terms of cooling capacity, the cooling benefit for an average resident is 2.2°C — compared to 3.4°C for a city dweller in the Global North.

“The differences are mostly due to quantity of vegetation, but efficiency of cooling is also better in the Global North — possibly due to management of green spaces and different tree species.”

Professor Jens-Christian Svenning, of the Center for Ecological Dynamics in a Novel Biosphere (ECONOVO) at Aarhus University, said: “The good news is that this nature-based solution to cooling can be substantially improved across the Global South, helping to tackle future heat stress for billions of people.”

Professor Rob Dunn, of North Carolina State University, said: “It won’t be easy to regreen cities. It can be expensive in the short-term. Yet, it will be key to making cities liveable in the immediate future. Also key will be working to prevent the loss of green space in those cities that have it, or at least that have a little.

“Changes could include ground-level green spaces and vertical and rooftop gardens, or even forests, to help protect city people from extreme heat.”

The common idea of global water supply is rain falling on the earth’s surface and then stored in aquifers, lakes, and rivers. This idea is usually used to assess water security and the risk of water scarcity. However, a new study published in Nature Water shows how the water risks are dependent on governance and environmental conditions present upwind, which means the areas where the moisture for rain comes from.

“Water supply really originates beforehand, with moisture evaporated from land or in the ocean traveling in the atmosphere before falling as rain. This upwind moisture is commonly overlooked when assessing water availability,” says Fernando Jaramillo, associate professor in physical geography at Stockholm University and responsible for the study.

When a lake or river is shared between different countries or authorities, assessments and regulations mainly apply an upstream perspective, considering conditions in the direction upriver from the water body. Instead, an upwind perspective considers the area where evaporated water is transported before ending up as rain. The area is known as a precipitationshed and can cover large areas of the earth’s surface.

“For instance, in tropical South America, most of the Amazon basin is downstream of the Andes mountain range, whereas large areas of the Andes are in themselves downwind of the Amazon rainforest and depending on it, which makes these two regions dependent on each other for water supply,” says Fernando Jaramillo.

The study examined 379 hydrological basins worldwide, revealing that risks to water security are significantly higher when considering the upwind origin of water.

“With this approach, we see that 32,900 km3/year of water requirements worldwide face very high risk, a near 50 percent increase, compared to the 20,500 km3/year resulting from the more traditional upstream focus,” says José Posada, former doctoral student at Stockholm University and main author of the study.

Political control can have major consequences

Since a large amount of water is evaporated from plants, changes in land use can affect downwind water availability. If deforestation and agricultural development are predominant in upwind areas, the amount of moisture vegetation provides may decrease, reducing rainfall downwind and increasing the risk to water security.

“For coastal countries such as the Philippines, most of the rain comes from the sea, which means that land-use changes pose very little risk to water security. Rainfall in inland countries such as Niger, on the other hand, comes mainly from moisture that evaporates in neighboring countries such as Nigeria and Ghana . This puts many land-locked countries at high risk regarding how water security is affected by changes in land use,” says Fernando Jaramillo.

In other words, political factors such as environmental management and regulations in areas where moisture first evaporates can affect water safety in completely different areas.

“For instance, the Congo River basin, heavily reliant on moisture from neighboring countries with low environmental performance and governance according to global indicators, faces considerable risks due to potential deforestation and unregulated land use changes in neighboring areas,” says Lan Wang-Erlandsson, researcher at the Stockholm Resilience Centre at Stockholm University and co-author of the study.

Environmental regulation requires an upwind perspective.

The study reveals why the lack of governability and environmental performance in a country upwind may be relevant to the water supply of a country downwind. It stresses the codependence between upstream/downwind and downstream/upwind countries.

“It is not possible to ignore the interdependence between countries. In the end, all water is connected, so we should not only mind how we manage our water resources within a region or country but also how our neighboring countries do,” says Lan Wang-Erlandsson.

“We hope that the findings of this study can help identify where and to whom cooperation strategies and efforts can be directed to mitigate the causes of water-related tensions, including atmospheric water flows in transboundary decision-making and water governance frameworks. We stress the need for international cooperation to effectively manage upwind moisture sources,” concludes Fernando Jaramillo.