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An astrocytic pH regulator that can repair the blood-brain barrier and reverse brain damage caused by ischemic stroke

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An astrocytic pH regulator that can repair the blood-brain barrier and reverse brain damage caused by ischemic stroke


Ischemic stroke is a leading cause of death and disability, affecting about 15 million worldwide each year. Among the various factors contributing to the pathogenesis of this condition is the loss of the blood-brain barrier, a highly selective protective cellular barrier that prevents harmful chemicals from entering the brain through the blood. Understanding the mechanisms that regulate the integrity of the blood-brain barrier, developing strategies to repair it, and reversing brain damage will have far-reaching benefits for patients suffering from stroke and related neurological conditions.

A recent study from the laboratory of Dr. Hyun Kyoung Lee, associate professor at Baylor College of Medicine and an investigator at the Jan and Dan Duncan Neurological Research Institute (Duncan NRI) at Texas Children’s Hospital, has found that an ion transporter protein that regulates the pH of specific brain cells can repair the blood-brain barrier and restore normal brain function after ischemic stroke.

The study, published in Cell Reports, is the first to reveal novel and specific therapeutic targets for ischemic stroke and related brain conditions for which no targeted treatments exist currently.

The blood-brain barrier and pH regulation are disrupted in stroke and other neurological conditions

“Disruption of blood-brain barrier integrity is a pathophysiological hallmark of stroke and several devastating neurological disorders,” Dr. Lee, a Cynthia and Anthony G. Petrello Endowed Scholar in Neurological Research, said. “A damaged blood-brain barrier often leads to severe consequences such as brain edema, neuronal damage, and eventually, motor and cognitive deficits. Very little was known about how stroke damages the blood-brain barrier prior to this study.

While endothelial cells form the core of the blood-brain barrier, emerging evidence suggests astrocytes, which are the most abundant and diverse type of support cells in the central nervous system, play a critical role in maintaining the integrity of this structure.

In addition to this barrier, a strict balance of pH (a measure of acidity or alkalinity of a solution) within the brain cells and their surrounding environment is crucial for optimal brain function. Dysregulation of pH homeostasis in the brain is often implicated in a range of neurological conditions.

Ischemic stroke injury is associated with a drastic reduction in pH. However, until this study, the precise reason for this alteration and the role of astrocytes in this process was not known.

Astrocytic Slc4a4 plays a critical role in the maintenance of the blood-brain barrier

Previous studies have demonstrated that a sodium-carbonate cotransporter 1 (Slc4a4), which is enriched in the astrocytes, is responsible for shuttling acid-base ions across the cell membrane in a bidirectional manner to regulate both intra- and extracellular pH in response to internal and external stimuli. Moreover, patients with Slc4a4 variants have been associated with many brain disorders, including ischemic stroke.

This is the first study to investigate whether and how Slc4a4 governs astrocyte-endothelial cell interaction in blood-brain barrier maintenance and repair after stroke.

To test the biological role of Slc4a4, the Duncan NRI team generated a conditional mouse model of Slc4a4 using which they could specifically delete the expression of this gene in the brain astrocytes during development and in adult mice.

Using this mouse model, they found that deleting Slc4a4 from astrocytes altered their structure and function. “We found that the brain vasculature was altered in the absence of astrocytic Slc4a4 — there was >40% increase in the diameter of the blood vessels in the brain, a three-fold increase in the number of small molecules that were able to infiltrate the brain along with the loss of junctional markers — which together provided compelling evidence that the blood-brain barrier was disrupted in the absence of astrocytic Slc4a4 in these mice,” Dr. Qi Ye, lead author and postdoctoral fellow in the Lee lab said.

Slc4a4 is critical for remodeling the blood-brain barrier after ischemic stroke

To test if astrocytic Slc4a4 was important for remodeling the blood-brain barrier after ischemic stroke, they used a cortical photothrombotic stroke model in Slc4a4 animal models. This stroke injury model in animals closely mimics the size, location, as well as reactive gliosis, a scar-like inflammatory response to ischemic stroke injury in human brains.

In this model using multi-omics analyses, they found that loss of astrocytic Slc4a4 increased the secretion of a CCL2, a pro-inflammatory molecule, which activated the CCR2 receptor present on the nearby endothelial cells to increase permeability, damaging the blood-brain barrier and increasing leakage between the two cell types. Finally, they found this breakdown of the blood-brain barrier was mediated by increased levels of specific metabolites (arginine and nitrous oxide) caused by changes in astrocytic pH levels.

“By revealing the precise mechanism and key players involved in the breakdown of the blood-brain barrier after stroke, this study has opened potential new avenues to treat ischemic stroke and several associated brain pathologies,” Dr. Lee said. “It is promising that key players identified in this pathway — the Slc4a4 transporter protein, the CCL2-CCR2 axis as well the metabolites — are ‘druggable’ and can be developed into potential therapeutic targets.”



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Orchids support seedlings through ‘parental nurture’ via shared underground fungal networks

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Orchids support seedlings through ‘parental nurture’ via shared underground fungal networks


The Common Spotted Orchid (Dactylorhiza fuchsii) is found all over the UK. These orchids produce tiny seeds that can be carried anywhere by the wind, yet they often appear in clumps with small seedlings growing near mature plants. This phenomenon has puzzled ecologists since Darwin’s time, with the exact reason remaining a mystery.

A new study, led by researchers from the University of Sheffield in collaboration with The University of Manchester, provides the first evidence that early stage orchid seedlings germinate and thrive near to adult plants due to a kind of parental nurture using underground fungal networks.

Scientists investigated the idea that fungal networks, known as mycorrhizal networks, act as a direct pathway for established orchid plants to share recently produced sugars with developing seedlings.

Professor Katie Field, co-author of the study and Professor of Plant-Soil Processes at the University of Sheffield’s School of Biosciences, said: “Our results support the idea that some orchids engage in a form of ‘parental nurture’ with their seedlings. By supplying early stage seedlings with essential nutrients via shared fungal connections, the parent orchids give the seedlings an advantage over neighbouring plants that are competing for the same resources.

“This finding is exciting because why these orchids are often found in clumps, despite their seeds being wind dispersed, has been a puzzle for hundreds of years.”

The study focused on the Common Spotted Orchid and its fungal partner, Ceratobasidium cornigerum. Researchers created a system where mature, green orchids were connected to developing, chlorophyll-free seedlings through a fungal network grown on agar.

The mature plants were then exposed to a special form of carbon dioxide that could be tracked within the system.

Here’s how it worked:

  • Green orchid plants were connected to developing seedlings through the fungal network.
  • The green plants were then exposed to a special form of carbon dioxide that could be tracked within the system.
  • After a period of time, the researchers analysed both the seedlings and the fungal network to see where the labelled carbon ended up.

The results were clear, the seedlings were accumulating the labelled carbon, indicating they were being supported by the adult plants. By tracking the movement of carbon, the study showed that the mature orchids were indeed sharing their recently produced sugars with the seedlings through the fungal network.

Sir David Read, Emeritus Professor of Plant Sciences from the University of Sheffield and lead author of the study, said: “Whereas the seeds of most plants, for example legumes (peas, beans) and grasses (rice, corn, wheat) are fully provisioned with food reserves by their parent plants, the so-called dust seeds of orchids receive insufficient reserves from the parents to develop on their own.

“They are instead produced in their millions by each individual parent orchid plant from which they are dispersed, by wind, to the surrounding environment. Even Charles Darwin was puzzled by this strategy, suggesting that while it should enable the seeds of an individual orchid plant to be so widely distributed that within a few years it could colonise the whole world. He observed that their failure to do so ‘could not be understood at this time’.

“What is now revealed is that the belowground development of these essentially reserve-free seeds can be supported by photosynthetically produced sugars that are transported to them from mature plants growing above ground through a shared mycelium of symbiotic fungi.”

Results of the study, published in New Phytologist, show the amount of carbon transferred seemed to depend on the environment. When the fungus had access to a richer food source (oatmeal agar), less carbon was transferred to the seedling. This suggests that the strength of the demand from the seedlings may influence the flow of nutrients through the network.

This research has important implications for understanding orchid ecology and conservation efforts. By recognising the importance of fungal connections, scientists can develop better strategies for protecting these unique and often threatened plants.

Next steps are to research this theory in the natural habitat that the orchids are found in and to look at whether this applies to other species.



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Bird flu: Diverse range of vaccines platforms ‘crucial’ for enhancing human pandemic preparedness

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Bird flu: Diverse range of vaccines platforms ‘crucial’ for enhancing human pandemic preparedness


Vaccination remains the most effective strategy for avian influenza prevention and control in humans, despite varying vaccine efficacy across strains.

That’s according to the authors of a new review which delves into existing research into bird flu vaccines for humans.

Published in the peer-reviewed journal Human Vaccines & Immunotherapeutics, the results of the paper are particularly timely following news last week (Wednesday 22nd May) that the bird flu strain H5N1 had once again, for a second time, jumped from cattle in America to a human — prompting fears of subsequent human-to-human infection, with possible critical consequences.

Instances of the avian influenza were first recognized in US cattle in March. Since then, this strain has mainly spread from cow-to-cow and scientists have discovered very high levels of virus in raw milk (pasteurized milk is safe, having shown viral RNA but not infectious virus). To-date two people, however, are known to have contracted the bird flu virus. Both patients — US farmers — only reported eye symptoms and with treatment they made a full recovery.

Following tests on the first human instance, it was seen that the strain had mutated to be better adapted to mammalian cells, but as long as that human didn’t pass it onto another person it likely stopped the spread at that point. With the second case, the CDC has released a statement to say it has been monitoring influenza surveillance systems intently, especially in impacted states. “There has been no sign of unusual influenza activity in people, including in syndromic surveillance,” they report.

The concern now, though, is that if H5N1 continues to be given the environment in which to mutate (such as in close quarter cattle farms) — and this continues long enough — it has the potential to find a combination that will easily spread to humans.

The results of this new research, carried out by a team at the University of Georgia, USA, suggests vaccines still remain our “primary defense” against potential spread of avian influenzas such as the H5N1 and others assessed.

“The H5N1, H7N9, and H9N2 subtypes of avian influenza virus pose a dual threat, not only causing significant economic losses to the global poultry industry but also presenting a pressing public health concern due to documented spillover events and human cases,” explains lead author Flavio Cargnin Faccin, who alongside his mentor Dr. Daniel Perez of the University of Georgia, USA, analyzed the current landscape of research into human vaccines for these bird flus.

“This deep delve into the landscape of avian influenza vaccines for humans shows vaccination remains the primary defense against the spread of these viruses.”

The team examined studies of vaccines tested in mice, ferrets, non-human primates, and clinical trials of bird flu vaccines in humans, and assessed both established platforms and promising new directions.

The review carried out suggests inactivated vaccines are a safe and affordable option that primarily activate humoral immunity — the part of our immune system that produces antibodies.

Live attenuated influenza vaccines (LAIVs) are known to induce a wider immune response than inactivated vaccines, activating not only antibody production but also mucosal and cellular defenses. In this review, the authors suggest this broader response may offer greater protection, though, the authors suggest further research is needed to fully understand and harness its potential benefits for both human and agricultural applications.

The review also examined alternatives, such as virus-like particle (VLP) vaccines and messenger RNA (mRNA) vaccines, that have emerged more recently. Although VLP vaccines for bird flu have limited clinical trial data in humans, results from studies in mice and ferrets showed promise, the authors found. mRNA vaccines against H5N1 and H7N9 bird flu subtypes also generated a rapid and strong immune response in mice and ferrets, and, while data in humans is scarce, results from a phase 1 study of an H7N9 mRNA vaccine in healthy humans were “encouraging.”

Overall, the team suggests “exploring and employing a diverse range of vaccine platforms,” will be “crucial for enhancing pandemic preparedness and mitigating the threat of avian influenza viruses.”



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When should you neuter or spay your dog?

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When should you neuter or spay your dog?


Researchers at the University of California, Davis, have updated their guidelines on when to neuter 40 popular dog varieties by breed and sex. Their recent paper in Frontiers in Veterinary Science adds five breeds to a line of research that began in 2013 with a study that suggested that early neutering of golden retrievers puts them at increased risk of joint diseases and certain cancers.

That initial study set off a flurry of debate about the best age to neuter other popular breeds. Professors Lynette and Benjamin Hart of the School of Veterinary Medicine, the study’s lead authors, set out to add more breed studies by examining more than a decade of data from thousands of dogs treated at the UC Davis veterinary hospital. Their goal was to provide owners with more information to make the best decision for their animals.

They specifically looked at the correlation between neutering or spaying a dog before 1 year of age and a dog’s risk of developing certain cancers. These include cancers of the lymph nodes, bones, blood vessels or mast cell tumors for some breeds; and joint disorders such as hip or elbow dysplasia, or cranial cruciate ligament tears. Joint disorders and cancers are of particular interest because neutering removes male and female sex hormones that play key roles in important body processes such as closure of bone growth plates.

For the most recent study, they focused on German short/wirehaired pointer, mastiff, Newfoundland, Rhodesian ridgeback and Siberian husky. Data was collected from the UC Davis veterinary hospital’s records that included more than 200 cases for each of these five breeds weighing more than 20 kg (or 44 pounds), spanning January 2000 through December 2020.

The Harts said their updated guidelines emphasize the importance of personalized decisions regarding the neutering of dogs, considering the dog’s breed, sex and context. A table representing guidelines reflecting the research findings for all 40 breeds that have been studied, including the five new breeds, can be found here.

Health risks different among breeds

“It’s always complicated to consider an alternate paradigm,” said Professor Lynette Hart. “This is a shift from a long-standing model of early spay/neuter practices in the U.S. and much of Europe to neuter by 6 months of age, but important to consider as we see the connections between gonadal hormone withdrawal from early spay/neuter and potential health concerns.”

The study found major differences among these breeds for developing joint disorders and cancers when neutered early. Male and female pointer breeds had elevated joint disorders and increased cancers; male mastiff breeds had increased cranial cruciate ligament tears and lymphoma; female Newfoundland breeds had heightened risks for joint disorders; female Ridgeback breeds had heightened risks for mast cell tumors with very early neutering; and Siberian huskies showed no significant effects on joint disorders or cancers.

“We’re invested in making contributions to people’s relationship with their animals,” said Benjamin Hart, distinguished professor emeritus. “This guidance provides information and options for veterinarians to give pet owners, who should have the final decision-making role for the health and well-being of their animal.”

Their combined research studies will soon be available with others in the open access journal, Frontiers of Veterinary Science, as a free e-book, Effective Options Regarding Spay or Neuter of Dogs.

Other researchers on this UC Davis study include: Abigail Thigpen, Maya Lee, Miya Babchuk, Jenna Lee, Megan Ho, Sara Clarkson and Juliann Chou with the School of Veterinary Medicine; and Neil Willits with the Department of Statistics.

The research received a small amount of funding from the Center for Companion Animal Health, but was primarily conducted by the above authors as volunteers.



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