New study shows that stroke byproduct acrolein activates the precursor of heparanase, an enzyme that degrades the glycocalyx in the blood-brain barrier
Strokes are a leading cause of poor quality of life or even death in Japan and the world over. Since its characterization, several researchers have been working tooth and nail to identify drug-accessible and effective therapeutic targets for this debilitating condition. One such region of interest for drug targets is the blood-brain barrier (BBB).
The BBB is a structure located around the brain, which prevents the entry of unnecessary circulating cells and biomolecules into the brain. The blood vessels in the BBB are coated with a distinct and protective layer of sugar, called the endothelial glycocalyx, which prevents their entry. However, in the event of a stroke, which results in the blockage or severance of blood vessels in the brain, studies have shown that this glycocalyx and, in turn, the integrity of the BBB, get compromised. In addition, damage to the blood vessels leads to neuronal death and the build-up of toxic byproducts like acrolein.
A group of researchers from Japan and the United States wanted to explore how the degradation of the glycocalyx takes place during an ischemic stroke. Junior Associate Professor Kyohei Higashi from Tokyo University of Science, one of the researchers, explains the motivation behind the research, “When brain tissue becomes necrotic due to ischemia, the function of the BBB is disrupted and immune cells infiltrate the brain, exacerbating inflammation, but the details of this process are still unclear.” For the first time, as detailed by the study published in Journal of Biological Chemistry, the group of scientists, led by Dr. Higashi, have identified a possible mechanism that links acrolein accumulation to glycocalyx modifications, which results in damage to the BBB. The team, also comprising Naoshi Dohmae and Takehiro Suzuki from RIKEN Center for Sustainable Resource Science, Toshihiko Toida from Chiba University, Kazuei Igarashi from Amine Pharma Research Institute, Robert J. Linhardt from Rensselaer Polytechnic Institute, and Tomomi Furihata from Tokyo University of Pharmacy and Life Sciences, used mouse models of stroke as well as in vitro (“in the lab”) experiments using cerebral capillary endothelial cells to accurately study the mechanisms behind the breakdown of the BBB.
The researchers initially identified that the major sugars in the glycocalyx, heparan sulphate and chondroitin sulfate, showed decreased levels in the ‘hyperacute phase’ after a stroke. They also found the increased activity of glycocalyx-degrading enzymes like hyaluronidase 1 and heparanase. Upon further in vitro investigation using cell lines, they found that acrolein exposure led to the activation of the precursor of heparanase (proHPSE). Specifically, they found that the acrolein modified specific amino acids on the structure of proHPSE, activating it. They concluded that this mechanism possibly led to the degradation of the glycocalyx, and the subsequent disruption of the BBB.
The team’s discovery is critical, as the acrolein-modified proHPSE could be a novel and potentially effective drug target for post-stroke inflammation. As Dr. Higashi, who is also the corresponding author of the study, speculates, “Because proHPSE, but not HPSE, localizes outside cells by binding with heparan sulfate proteoglycans, acrolein-modified proHPSE represents a promising target to protect the endothelial glycocalyx.”
Indeed, we hope that the further investigation of this mechanism would lead us to therapies that are more effective in tackling stroke-related illnesses!
About The Tokyo University of Science
Tokyo University of Science (TUS) is a well-known and respected university, and the largest science-specialized private research university in Japan, with four campuses in central Tokyo and its suburbs and in Hokkaido. Established in 1881, the university has continually contributed to Japan’s development in science through inculcating the love for science in researchers, technicians, and educators.
With a mission of “Creating science and technology for the harmonious development of nature, human beings, and society”, TUS has undertaken a wide range of research from basic to applied science. TUS has embraced a multidisciplinary approach to research and undertaken intensive study in some of today’s most vital fields. TUS is a meritocracy where the best in science is recognized and nurtured. It is the only private university in Japan that has produced a Nobel Prize winner and the only private university in Asia to produce Nobel Prize winners within the natural sciences field.
About Dr. Kyohei Higashi
Dr. Kyohei Higashi is a Junior Associate Professor at Tokyo University of Science, Japan. His areas of research interest include the physiological function of polyamines, acute cerebral infarction, and structures of glycosaminoglycans derived from biological samples.
This study was supported by a Grant-in-Aid for Scientific Research (C) (15K08068) from the Japan Society for the Promotion of Science, the Research Foundation for Pharmaceutical Sciences, and the Chiba Foundation for Health Promotion and Disease prevention, to Junior Associate Professor Kyohei Higashi. In addition, this study was supported by the Smoking Research Foundation, to Professor Toshihiko Toida.
Climate change atlas offers a glimpse into forest futures
Delaware, Ohio, April 21, 2021– For 20 years, the USDA Forest Service’s Climate Change Atlas has been giving foresters in the Eastern United States insight into how future habitat conditions may affect tree species, from dramatic change (a big increase of cedar elm, for example, and a big loss in balsam poplar) to the fairly neutral (red maple). The Forest Service scientists who designed the Climate Change Atlas recently completed a major overhaul of the online tool, including new predictor variables, an updated modeling framework, updated data, information on potential migration, and a revised series of four tutorials on how to use the Atlas.
The Climate Change Atlas offers a glimpse into possible futures for 125 eastern tree species by combining modeling for species distribution, migration, and tree species traits. Modeling is provided for trees assuming moderate and high emissions of greenhouse gases. The Atlas uses data collected by the Forest Service’s Forest Inventory and Analysis (FIA) Program from 3.9 million trees from 85,000 inventory plots in the Eastern United States.
“Science-based forest management offers a natural solution to climate change in the United States, and our challenge is to not only develop that science but to package it in formats that are convenient, accurate, and useful to forest managers,” said Cynthia West, Director of the Northern Research Station and the Forest Products Laboratory. “The Climate Change Atlas exemplifies how Forest Service research serves land managers in our region.”
Updates to the Climate Change Atlas include place-based summaries of current tree species ranked in order of importance, potential tree species shifts within the area, and potential species to consider for planting for individual national forests, national parks, urban areas, ecoregions, watersheds as well as full coverage by 1×1 degree grids, across the Eastern United States.
The Atlas was created by Northern Research Station scientists Louis Iverson, Anantha Prasad, Matthew Peters, and Stephen Matthews.
Warming seas might also look less colorful to some fish. Here’s why that matters.
Climate change is driving some fish into cooler, deeper waters. Now they may be faced with another challenge: how to make sense of a world drained of color.
DURHAM, N.C. — When marine biologist Eleanor Caves of the University of Exeter thinks back to her first scuba dives, one of the first things she recalls noticing is that colors seem off underwater. The vivid reds, oranges, purples and yellows she was used to seeing in the sunlit waters near the surface look increasingly dim and drab with depth, and before long the whole ocean loses most of its rainbow leaving nothing but shades of blue.
“The thing that always got me about diving was what happens to people’s faces and lips,” said her former Ph.D. adviser Sönke Johnsen, a biology professor at Duke University. “Everybody has a ghastly sallow complexion.”
Which got the researchers to thinking: In the last half-century, some fish have been shifting into deeper waters, and climate change is likely to blame. One study found that fish species off the northeastern coast of the United States descended more than one meter per year between 1968 and 2007, in response to a warming of only about one degree Celsius.
Could such shifts make the color cues fish rely on for survival harder to see?
Previous research suggests it might. Scientists already have evidence that fish have a harder time discerning differences in each other’s hues and brightness in waters made murkier by other causes, such as erosion or nutrient runoff.
As an example, the authors cite studies of three-spined sticklebacks that breed in the shallow coastal waters of the Baltic Sea, where females choose among males — who care for the eggs — based on the redness of their throats and bellies. But algal blooms can create cloudy conditions that make it harder to see, which tricks females into mating with less fit males whose hatchlings don’t make it.
The turbidity makes it harder for a male to prove he’s a worthy mate by interfering with females’ ability to distinguish subtle gradations of red or orange, Johnsen said. “For any poor fish that has beautiful red coloration on his body, now it’s like, ‘well, you’re just going to have to take my word for it.’”
Other studies have shown that, for cichlid fish in Africa’s Lake Victoria, where species rely on their distinctive colors to recognize their own kind, pollution can reduce water clarity to a point where they lose the ability to tell each other apart and start mating every which way.
The researchers say the same communication breakdown plaguing fish in turbid waters is likely happening to species that are being pushed to greater depths. And interactions with would-be mates aren’t the only situations that could be prone to confusion. Difficulty distinguishing colors could also make it harder for fish to locate prey, recognize rivals, or warn potential predators that they are dangerous to eat.
In a study published April 21 in the journal Proceedings of the Royal Society B, Caves and Johnsen used mathematical models to determine what the colors of the underwater world might look like as fish in the uppermost layer of the ocean shift to new depths.
They were able to show that, while the surface waters may be bursting with color, descending by just 30 meters shrinks the palette considerably.
“It’s like going back to the days of black and white TV,” Johnsen said.
When sunlight hits an object, some wavelengths are absorbed and others bounce off. It’s the wavelengths that are reflected back that make a red fish look red, or a blue fish blue. But a fish sporting certain colors at the surface will start to look different as it swims deeper because the water filters out or absorbs some wavelengths sooner than others.
The researchers were surprised to find that, especially for shallow-water species such as those that live in and around coral reefs, it doesn’t take much of a downward shift to have a dramatic effect on how colors appear.
“You really don’t have to go very far from the surface to notice a big impact,” said Caves, who will be starting as an assistant professor at the University of California, Santa Barbara, this fall.
Precisely which colors lose their luster first, and how quickly that happens as you go down, depends on what depths a species typically inhabits and how much deeper they are forced to go, as well as the type of environment they live in — whether it’s, say, the shallow bays or rocky shores of the Atlantic, or a tropical coral reef.
In clear ocean water, red is the first color to dull and disappear. “That’s important because so many species use red signals to attract mates or deter enemies,” Johnsen said.
The team predicts that some species will be more vulnerable than others. Take, for instance, fish that can’t take the edge off the heat by relocating toward the poles of the planet. Particularly in semi-enclosed waters such as the Mediterranean and Black seas or the Gulf of Mexico, or in coral reefs, which are stuck to the sea bed — these species will have no option but to dive deeper to keep their cool, Caves said.
As a next step, they hope to test their ideas in the coral reefs around the island of Guam, where butterflyfishes and fire gobies use their vivid color patterns to recognize members of their own species and woo mates.
“The problem is only accelerating,” Caves said. By the end of this century, it’s possible that sea surface temperatures will have heated up another 4.8 degrees Celsius, or an increase of 8.6 degrees Fahrenheit, compared to the 1896-2005 average.
And while warming is happening faster at the poles, “tropical waters are feeling the effects too,” Caves said.
This research was supported by the European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement (No 793454).
CITATION: “The Sensory Impacts of Climate Change: Bathymetric Shifts and Visually Mediated Interactions in Aquatic Species,” Eleanor Caves and Sönke Johnsen. Proceedings of the Royal Society B, April 21, 2021. DOI: 10.1098/rspb.2021.0396
Children exposed to intimate partner violence twice as likely to have poorer health
A new study has found up to half of all children with language difficulties and mental and physical health problems have been exposed to intimate partner violence, prompting calls for health and social care services to provide more effective identification and early intervention.
The research, led by the Murdoch Children’s Research Institute (MCRI) and published in The BMJ, showed children exposed to intimate partner violence from infancy were twice as likely to have a psychiatric diagnosis, emotional and behavioural difficulties, and impaired language skills at age 10. They were also more likely to have asthma and sleep problems.
The study also found that children exposed to intimate partner violence in the year they turned 10 were two to three times more likely to experience poor mental health, elevated blood pressure and sleep difficulties. But with the exception of language difficulties and asthma, child health outcomes at age 10 were not affected if their only exposure to intimate partner violence occurred before they turned five, highlighting the need for more effective early intervention.
The research involved 1507 first-time mothers and their first-born children. Women were recruited to the study from six public maternity hospitals in Melbourne. More than one in four women and children in the study were exposed to intimate partner violence during the first 10 years after the child’s birth.
MCRI Professor Stephanie Brown said the findings showed the size of the burden of ill health carried by children growing up in households where intimate partner violence occurred.
“Intimate partner is the most common form of violence against women and their children and is a global public health issue,” she said. “It’s not limited to physical and sexual violence and is often characterised by a pattern of psychological control and coercion. Children may pick up on this and experience constant fear or anxiety at home.
“The impact of COVID-19 has increased pressures on families and heightened the need for more effective intervention and support for women and children experiencing domestic abuse.”
Professor Brown said that many women experiencing intimate partner violence were unsure about seeking support from family health and social care services.
“Services need to aware of the impact of intimate partner violence on children’s health and wellbeing and work to overcome barriers that may get in the way of women seeking support for themselves and their children,” she said.
“Barriers may include fear of judgement, the perception that health services can’t help, the cost of GP appointments, limited availability of low cost psychological and other allied health services, and lack of services that take a holistic approach to women and children’s health and wellbeing.
“If child health and social services do not recognise and respond to intimate partner violence as a potential contributing factor to poor child health outcomes, interventions to support children with health and developmental problems are likely to be less effective.”
MCRI Dr Deirdre Gartland said some mothers and children experience good health and wellbeing despite their exposure to intimate partner violence.
“It is important to recognise that not all children exposed to intimate partner violence have poor physical and mental health,” she said.
“Women are doing everything they can to protect and look after their children to give them the best possible outcomes despite the situations they are in.”
Researchers from The University of Melbourne, La Trobe University, The Royal Women’s Hospital, Queensland University of Technology, Griffith University and Deakin University also contributed to the findings.
Publication: Deirdre Gartland, Laura J Conway, Rebecca Giallo, Fiona K Mensah, Fallon Cook, Kelsey Hegarty, Helen Herrman, Jan Nicholson, Sheena Reilly, Harriet Hiscock, Emma Sciberras and Stephanie J Brown. ‘Intimate partner violence and child outcomes at age 10: a pregnancy cohort,’ The BMJ. DOI: 10.1136/archdischild-2020-320321
*The content of this communication is the sole responsibility of MCRI and does not reflect the views of the NHMRC.
Available for interview:
Professor Stephanie Brown, MCRI Group Leader, Ingenerational Health
Dr Deirdre Gartland, MCRI Team Leader, Ingenerational Health
The Maternal Health Study was supported by project grants from the Australian National Health and Medical Research Council (NHMRC; #199222, #433006 and #491205) and Australian Rotary Health. Stephanie Brown holds an NHMRC Senior Research Fellowship (#1103976). Rebecca Giallo, Fiona Mensah and Emma Sciberras hold NHMRC Career Development Fellowships (#1123900, #1111160 and #1110688). Emma Sciberras holds a Veski Inspiring Women’s Fellowship. Harriet Hiscock holds an NHMRC Practitioner Fellowship (#1136222). Deirdre Gartland and Laura Conway are supported by the NHMRC Safer Families Centre (#1116690). Laura Conway and Fallon Cook hold Lifecourse Postdoctoral Fellowships supported by The Royal Children’s Hospital Research Foundation. Research at the Murdoch Children’s Research Institute is supported by the Victorian Government Operational Infrastructure Support Programme.
Large NIH clinical trial will test polyclonal antibody therapeutic for COVID-19
A Phase 2/3 trial to evaluate a new fully-human polyclonal antibody therapeutic targeted to SARS-CoV-2, called SAB-185, has begun enrolling non-hospitalized people with mild or moderate cases of COVID-19. The trial, ACTIV-2, is sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health. The therapeutic was developed by SAB Biotherapeutics, Inc. (Sioux Falls, South Dakota).
NIH’s Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) program is a public-private partnership to develop a coordinated research strategy for speeding development of the most promising treatments and vaccine candidates. ACTIV-2 is a master protocol designed for evaluating multiple investigational agents in adults with mild-to-moderate COVID-19 who are not hospitalized. Led by the NIAID-funded AIDS Clinical Trials Group (ACTG) and supported by PPD (Wilmington, North Carolina), a global contract research organization that is responsible for trial execution, the trial will enroll participants at sites around the world.
The ACTIV-2 study design allows researchers to evaluate SAB-185 in a small group of volunteers and then continue testing it in a larger group if the antibody appears safe and effective. The trial began on August 4, 2020 and has since added several therapeutics for testing.
SAB-185 is a fully-human polyclonal antibody therapeutic candidate for COVID-19 that has completed enrollment of Phase 1 and Phase 1b clinical studies. In previous pre-clinical studies, SAB-185 demonstrated neutralization of live SARS-CoV-2 at titers higher than convalescent plasma. The therapeutic candidate was developed from SAB’s platform, which uses genetically engineered cattle to produce fully-human antibodies in a process designed to potentially be both scalable and reliable.SAB-185 is administered intravenously, with the dose depending on the patient’s weight in kilograms (kg). A high and a low dose of SAB-185 will be tested in this trial.
When participants enroll in ACTIV-2, they will be assigned at random to receive either SAB-185, another therapeutic currently being evaluated in ACTIV-2, or a placebo. Other therapeutics currently being evaluated in ACTIV-2 include:
- a regimen of two experimental antibodies, BRII-196 and BRII-198, developed by Brii Biosciences based in Durham, North Carolina and Beijing, China
- SNG001, an inhalable beta interferon developed by Synairgen based in Southampton, United Kingdom
- AZD7442, a long-acting monoclonal antibody combination administered by either an intravenous infusion or an intramuscular injection, developed by AstraZeneca based in Cambridge, United Kingdom
- Camostat mesilate, an orally administered serine protease inhibitor developed by Sagent Pharmaceuticals based in Schaumburg, Illinois.
In the Phase 2 evaluation, each agent tested in ACTIV-2, and the shared placebo group, will enroll 110 participants with mild or moderate COVID-19 who are at risk for disease progression. The trial is blinded, so neither participants nor investigators will know whether a participant is receiving the therapeutic or the placebo. Participants will attend a series of clinic or at-home visits by clinicians and will be followed for a total of 72 weeks.
An independent Data and Safety Monitoring Board (DSMB) overseeing the trial will review the data collected at 28 days. They will monitor data to see if the therapy is safe, reduces the duration of COVID-19 symptoms and eliminates virus from the body. If there are no serious safety concerns and the results of this Phase 2 study seem promising, the trial will transition to Phase 3. It will then enroll 421 additional volunteers to receive the SAB agent, and 421 volunteers in the placebo group. The primary objective of the Phase 3 trial is to determine if the SAB therapy prevents either hospitalization or death by 28 days after study entry.
The study team for ACTIV-2 is led by protocol chairs Kara W. Chew, M.D., of the University of California, Los Angeles (UCLA), and Davey Smith, M.D., of the University of California, San Diego. Eric S. Daar, M.D., of UCLA, and David Wohl, M.D., of the University of North Carolina at Chapel Hill (UNC), serve as protocol vice-chairs. Babafemi Taiwo, MBBS of Northwestern University is a co-investigator focused on the SAB agent. The ACTG network is led by chair Judith Currier, M.D., (UCLA) and vice-chair Joseph Eron, M.D., of UNC.
For more information on this study, please visit http://www.
NIAID conducts and supports research–at NIH, throughout the United States, and worldwide–to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID website.
About the National Institutes of Health (NIH): NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.
NIH…Turning Discovery Into Health®
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