Can Leukemia in Children With Down Syndrome be Prevented? (Medicine)

Princess Margaret Scientists reveal a new target that suggests it can

For the first time, Princess Margaret researchers have mapped out where and how leukemia begins and develops in infants with Down syndrome in preclinical models, paving the way to potentially prevent this cancer in the future.

Children with Down syndrome have a 150-fold increased risk of developing myeloid leukemia within the first five years of their life. Yet the mechanism by which the extra copy of chromosome 21 predisposes to leukemia remains unclear.

Down syndrome is a genetic disorder caused by a random error in cell division in early human development that results in an extra copy of chromosome 21. This extra copy is what causes the developmental changes and physical traits associated with the syndrome, including the predisposition to leukemia.

However, the exact blood cell type in which leukemia begins in fetal development, along with the genetic alterations that cause this cell to become preleukemic, has eluded researchers until now. Furthermore, the additional mutations that must accumulate during childhood to transform preleukemia into acute leukemia were unknown.

The study and results of the early evolution of leukemia in Down syndrome from the laboratory of Princess Margaret Senior Scientist Dr. John Dick are published in Science, July 9, 2021. Post-doctoral fellow Dr. Elvin Wagenblast is first author, and Affiliate Scientist Dr. Eric Lechman is co-senior author, along with Dr. Dick.

Dr. Eric Lechman, Affiliate Scientist at the Princess Margaret Cancer Centre, University Health Network, is co-senior author. © UHN

“A whole sequence of cellular events have already happened before a person is diagnosed with the disease,” explains Dr. Dick. “You can’t tell at that point which sequence of events happened first, you just know that it has already happened.

“For the first time, our model is giving us insight into the human leukemia process. Ultimately, we may be able to prevent the acute illness by treating it in its earliest phase, when it is preleukemic, to prevent its progression to full blown leukemia.”

Using a preclinical model that includes human Down syndrome cells from a human tissue biobank, along with an enhanced CRISPR/Cas9 method for gene alteration in human blood stem cells that was developed by Drs. Wagenblast and Lechman at Princess Margaret, the team set out to chart the steps involved in this specific leukemia evolution.

Transient preleukemia is a unique condition frequently occurring in newborns with Down syndrome, which can either spontaneously disappear within days to months of birth, or transform into acute myeloid leukemia within four years by acquiring additional mutations in some individuals.

What Drs. Wagenblast, Lechman and Dick revealed in this work was the distinct cellular and genetic events related to transient preleukemia, from their beginnings in the fetus, to further progression to leukemia in childhood.

Dr. John Dick, Senior Scientist at the Princess Margaret Cancer Centre, University Health Network, is co-senior author. © UHN

Specifically, the team was able to test a variety of blood cell types and pinpoint that transient preleukemia originates only from long-term hematopoietic stem cells (HSCs), with the GATA1 mutation, as early as the second trimester of a fetus with Down syndrome. Preleukemia does not begin in HSCs from non-Down syndrome samples.

Only HSCs are able to regenerate the entire blood system and maintain long-term output due to their unique continuous capacity for self-renewal. In a broader picture, the fact that the cellular origin of pediatric leukemia is limited to only long-term HSCs might have implications for other kinds of childhood leukemias beyond Down syndrome.

Acute leukemia happens only after the first two mutations – the extra copy of chromosome 21 and the GATA1 mutation – are in place and have “primed” the progeny or descendants downstream of the altered long-term HSCs to acquire further mutations that lead to fully transformed acute leukemia, explains Dr. Lechman.

“We actually created a human disease in a preclinical model by showing how the genetically edited, as well as the normal human blood stem cells, behave in it, and we succeeded in recreating the precise, progressive steps of how leukemia develops,” says Dr. Dick. “We now have a lot of clues as to the genetic abnormalities these mutations are driving when they cause leukemia.”

The team also identified CD117/KIT as a unique protein cell surface marker on the altered disease-driving stem cells that causes the cells to proliferate. In the preclinical model and setting, the researchers were able to target and eliminate preleukemic stem cells using small molecule CD117/KIT inhibitors to prevent their progression to acute leukemia.

The researchers note that this preventative strategy could potentially be used in Down syndrome newborns and even expanded to other childhood leukemias that are known to be initiated during fetal development.

“The clinical significance of being able to target pre-cancerous lesions and preventing progression to cancer is profound,” says Dr. Dick, “It would transform the pediatric cancer field.”

The work was supported by the Human Frontier Science Program, Alex’s Lemonade Stand Foundation, The Leukemia & Lymphoma Society and The Leukemia & Lymphoma Society of Canada, Portuguese Foundation for Science and Technology, Princess Margaret Cancer Centre Foundation, Ontario Institute for Cancer Research, Canadian Institutes for Health Research, International Development Research Centre, Canadian Cancer Society, Terry Fox Research Institute Program Project Grant, University of Toronto’s Medicine by Design.

Featured image: Dr. Elvin Wagenblast, Post-doctoral Fellow at the Princess Margaret Cancer Centre, University Health Network, is the first author. © UHN


Reference: Elvin Wagenblast, Joana Araújo, Olga I. Gan, Sarah K. Cutting, Alex Murison, Gabriela Krivdova, Maria Azkanaz, Jessica L. McLeod, Sabrina A. Smith, Blaise A. Gratton, Sajid A. Marhon, Martino Gabra, Jessie J. F. Medeiros, Sanaz Manteghi, Jian Chen, Michelle Chan-Seng-Yue, Laura Garcia-Prat, Leonardo Salmena, Daniel D. De Carvalho, Sagi Abelson, Mohamed Abdelhaleem, Karen Chong, Maian Roifman, Patrick Shannon, Jean C. Y. Wang, Johann K. Hitzler, David Chitayat, John E. Dick, Eric R. Lechman, “Mapping the cellular origin and early evolution of leukemia in Down syndrome”, Science  09 Jul 2021: Vol. 373, Issue 6551, eabf6202 DOI: https://doi.org/10.1126/science.abf6202


Provided by University Health Network

LHAASO’s Measurement Of Crab Nebula Brightness Yields New UHE Gamma-ray Standard (Planetary Science)

The Large High Altitude Air Shower Observatory (LHAASO), one of China’s key national science and technology infrastructure facilities, has accurately measured the brightness over 3.5 orders of magnitude of the standard candle in high-energy astronomy, thus calibrating a new standard for ultra-high-energy (UHE) gamma-ray sources. The standard candle is the famous Crab Nebula, which evolved from the “guest star” recorded by the imperial astronomers of China’s Song Dynasty.

LHAASO has also discovered a photon with an energy of 1.1 PeV (1 PeV = one quadrillion electronvolts), indicating the presence of an extremely powerful electron accelerator–about one-tenth the size of the solar system–located in the core region of the Crab Nebula. The accelerator can energize electrons to a level 20,000 times greater than what CERN’s Large Electron-Positron Collider (LEP) can ever achieve, thus approaching the absolute theoretical limit posed by classical electrodynamics and ideal magnetohydrodynamics.

Results will be published in Science on July 8. The LHAASO International Collaboration, which is led by the Institute of High Energy Physics of the Chinese Academy of Sciences, completed this study.

The Crab Nebula is 6,500 light-years from Earth. It was born in a bright supernova explosion in AD 1054. It is the first supernova remnant identified by modern astronomy with a clear historical record. The nebula harbors an energetic pulsar with a period of 30 milliseconds. The fast-rotating magnetosphere of the pulsar drives a powerful wind composed of electron-positron pairs moving at nearly the speed of light. The electrons/positrons in the pulsar wind further accelerate to higher energies once the wind encounters the ambient medium. The nebula is produced by the radiation of the accelerated electrons/positrons.

The Crab Nebula is one of the few sources that has been measured in all energy bands, i.e., radio, infrared, optical, ultraviolet, X-ray and gamma-ray. Its spectrum has been extensively studied for decades by many observers. As a bright and stable high-energy source, the Crab Nebula is regarded as the standard candle for many different energy bands. In this capacity, it serves as a reference for the measurement of other sources.

The Crab Nebula from the Nordic Optical Telescope (Image by Walter Nowotny)

LHAASO has measured the spectrum of the Crab Nebula at the highest-energy end, covering the broad range 0.0005-1.1 PeV. It has confirmed measurements from the past several decades. It has also achieved an accurate measurement in the UHE band (0.3-1.1 PeV) for the first time, thus calibrating the brightness of the standard candle over such an unprecedented energy range.

Among the 12 UHE gamma-ray sources discovered previously by LHAASO, the Crab Nebula was identified as one of two sources capable of emitting PeV photons, and is the only source with a definite astrophysical counterpart. The measured 1.1 PeV photon provides direct evidence for the acceleration of 2.3 PeV electrons in the source. Such an energy is about 20,000 times the maximum achievable energy of the most powerful man-made electron accelerator, the LEP, which is the predecessor of the LHC. Since high energy electrons suffer strong energy loss in a magnetic field, the accelerator in the Crab Nebula must operate at an incredibly high efficiency to balance the huge energy loss. According to the LHAASO measurement, its acceleration efficiency can reach 15% of the theoretical upper limit, thus surpassing that of the supernova blast wave by a factor of 1,000. This poses challenges to the standard paradigm of electron acceleration in high-energy astrophysics. An in-depth analysis and discussion of this topic are detailed in the current paper in Science.

LHAASO is a major national scientific and technological infrastructure facility focusing on cosmic ray observation and research. It is located at 4,410 meters above sea level on Mt. Haizi in Daocheng County, Sichuan Province and covers an area of about 1.36 km². It is composed of 5,195 electromagnetic particle detectors and 1,188 Muon detectors located in the square-kilometer complex array, a 78,000 m² water Cherenkov detector array, and 18 wide-field-of-view Cherenkov telescopes. Using these four techniques, LHAASO will be able to measure air showers generated by cosmic rays or gamma rays omnidirectionally with multiple variables simultaneously.

Basic information about the incident particles, such as arrival direction, type and energy, can be measured through the reconstruction of the showers. The newly published discovery demonstrates that LHAASO is capable of cross-checking measurements using multiple detection techniques, thus insuring reliable and accurate results. LHAASO will be completed this month and put into operation. With an expectation of detecting 1-2 photons with energies around 1 PeV from the Crab Nebula every year, the puzzle of the cosmic PeV electron accelerator will be unraveled in the coming years.

Featured image: Historical records of the guest star in 1054 © Image by Institute of High Energy Physics


Provided by Chinese Academy of Sciences

Can Microbes Combat Neurodegeneration? (Neuroscience)

Eran Blacher is the 2021 winner of the NOSTER & Science Microbiome Prize for his work in illuminating the relationship between the microbiome and neurodegenerative diseases such as Alzheimer’s disease (AD) and Amyotrophic Lateral Sclerosis (ALS).

The findings reveal new insights into the “gut-brain axis” and demonstrate that harnessing the microbiome and its associated metabolic pathways could provide a valuable approach to treating these and potentially other devastating neurological disorders.

Although millions of people worldwide suffer from neurodegenerative disorders, the roots of neurodegeneration remain unclear. A growing body of research consistently demonstrates that the human brain is inextricably linked to the gut microbiome, influencing brain activity in several ways. For example, small molecule metabolites produced by commensal bacteria can be absorbed into the bloodstream and reach the brain, where they can modulate the activity of brain cells, including neurons, astrocytes, and microglia.

In a mouse model, Blacher and colleagues investigated the role of the microbiome and its metabolites in ALS – a progressive neurodegenerative neuromuscular disease that affects nerve cells in the brain and spinal cord.

Blacher and the researchers depleted the microbiome of ALS-prone Sod1-Transgenic (Sod1-Tg) mice through wide-spectrum antibiotic treatment, discovering dysbiosis and microbiome-driven alterations in metabolite configuration preceding clinical ALS motor symptoms, as well as 11 distinct microbial strains correlated with disease severity.

Probiotic treatment of Sod1-Tg mice with either the gut microbe Akkermansia muciniphila or its associated metabolite, nicotinamide, improved ALS symptoms by significantly improving motor function and restored disrupted spinal cord gene expression patterns.

What’s more, in a preliminary observational study in humans, the researchers found similar, significant changes in the microbiome composition and function of ALS patients, associated with reduced nicotinamide levels in serum and cerebrospinal fluid.

“We posit that these findings are linked to our previous observations in mice and may lay the foundation of a larger clinical study in the future,” writes Blacher.

Finalists for the prize were Maria Zimmermann-Kogadeeva for her essay “Putting host-microbiota interactions in numbers,” and Erez Baruch for his essay “Gut microbiota modulation promotes response in immunotherapy-refractory melanoma patients.”


Reference: Eran Blacher, “Can microbes combat neurodegeneration?”, Science  09 Jul 2021: Vol. 373, Issue 6551, pp. 172-173. DOI: https://doi.org/10.1126/science.abi9353


Provided by AAAS

Skeletal Muscle Thermogenesis Keeps Chilly Sea Otters Warm (Biology)

Internal warmth through skeletal muscle thermogenesis enables sea otters – the smallest of marine mammals – to survive in their cold, marine habitats, researchers report.

The study provides insight into how the tiny creatures maintain a normal mammalian body temperature despite living their lives submerged in the chilly waters of the North Pacific Ocean.

Many marine animals that live in cold water environments are large and are often wrapped in a thick insulating layer of subcutaneous blubber to maintain a normal core body temperature.

On the other hand, sea otters lack both size and blubber and while their dense fur coat offers some insulation, it alone cannot offset heat loss into the surrounding cold waters.

To account for this, sea otters have a basal metabolic rate (BMR) approximately three times greater than is predicted for similar mammals their size. The tissue-level source of this hypermetabolism, however, is unknown. Because skeletal muscle is a major determinant of whole-body metabolism, Traver Wright and colleagues characterized respiratory capacity and thermogenic leak in sea otter muscle from captive-raised, stranded, and wild populations of northern and southern sea otters.

Wright et al. found that these otters are effectively internally warmed by way of thermogenic mitochondrial leak from skeletal muscle, and that this process could account for their observed hypermetabolism.

What’s more, the authors show that this muscle thermogenic capacity develops in neonates and reaches adult levels before mechanical function of the muscles matures, providing internal warmth from birth.

The study, “Skeletal muscle thermogenesis enables aquatic life in the smallest marine mammal”, published in Science on 9 July, 2021. DOI: https://doi.org/10.1126/science.abf4557


Provided by AAAS

Where Does the Shape Of the Romanesco Cauliflower Come From? (Botany)

The mystery of the formation of one of the most peculiar plant forms – the Romanesco cauliflower – has been solved by a team of scientists from the CNRS and Inria in an article published on the 9 July in Science.

Thanks to work combining mathematical modelling and plant biology, the scientists were able to determine that cauliflowers, and Romanescos in particular, are in fact buds that are designed to become flowers but which never reach their goal.

Instead, they develop into stems, which in turn continue trying to produce flowers. The cauliflower is born from this chain reaction, resulting in a succession of stems upon stems.

This study shows that the brief incursion of buds into a flowering state profoundly affects their functioning and allows them, unlike normal stems, to grow without leaves and to multiply almost infinitely.

The atypical shape of the Romanesco is explained by the fact that its stems produce buds more and more rapidly (whereas the production rate is constant in other cauliflowers). This acceleration gives each floret a pyramidal appearance, making the fractal aspect of the structure clear.

The study highlights how the selection of mutations in plants during the process of domestication has changed their shape, sometimes drastically, into the fruits and vegetables on our shelves.

Featured image: Photo of a Romanesco © Nathanael Prunet


Reference: Eugenio Azpeitia et al., “Cauliflower fractal forms arise from perturbations of floral gene networks”, Science  09 Jul 2021: Vol. 373, Issue 6551, pp. 192-197 DOI: 10.1126/science.abg5999


Provided by CNRS

Scientists Show How Light Therapy Treats Depression In Mice Model (Psychiatry)

Light activates the circadian clock gene Period1 in a brain region that affects the mood

Light therapy can help improve the mood of people with seasonal affective disorder (SAD) during short winter days, but exactly how this therapy works is not well understood. A new study by Urs Albrecht at the University of Fribourg, published July 8th in the journal PLOS Genetics, finds that light therapy’s beneficial effects come from activating the circadian clock gene Period1 in a part of the brain involved in mood and sleep-wake cycles.

Nighttime light has strong effects on the physiology and behavior of mammals. It can reset an animal’s circadian rhythms, and in the form of light therapy, affect mood in humans. Albrecht and his colleagues investigated how nighttime light impacts mood using mice as a model. They exposed mice to a pulse of light at different points during the night and then tested them for depressive behavior. The researchers discovered that light exposure at the end of the dark period–two hours before daytime–had an antidepressant effect on the animals. The pulse of light activated the Period1 gene in a brain region called the lateral habenula, which plays a role in mood. Light at other times, however, had no effect. When they deleted the Period1 gene, the mice no longer experienced the light’s beneficial effects.

The new results provide evidence that turning on Period1 in the lateral habenula is the key to light’s mood-boosting powers. The discovery that mice appeared to be less depressed when exposed to light at the end of the dark period than the beginning is similar to findings in humans. Light therapy is more efficient in the early morning than in the evening for patients with SAD. However, the researchers caution against making too many direct comparisons to humans since mice are nocturnal animals.

The researchers add, “Light perceived in the late part of the night induces expression of the clock gene Per1, which is related to improvement of depression like behavior in mice.”

In your coverage please use this URL to provide access to the freely available article in PLOS Geneticshttp://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1009625

Funding: This work was supported by the Velux Foundation (https://veluxstiftung.ch) Projects 995 and 772 to U.A. and the Swiss National Science Foundation (http://www.snf.ch) project number 310030_184667/1. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Featured image: Per1 gene expression (yellow color) before (left panel) and after a 15 minute light pulse (right panel) given in the dark at zeitgeber time 22 in the lateral habenula (area visualized by hatched lines). The blue color depicts cell nuclei. The white line bottom left indicates the scale and corresponds to 200 μm © Iwona Olejniczak, 2021, PLOS Genetics, CC-BY 4.0 (https://creativecommons.org/licenses/by/4.0/)


Reference: Olejniczak I, Ripperger JA, Sandrelli F, Schnell A, Mansencal-Strittmatter L, Wendrich K, et al. (2021) Light affects behavioral despair involving the clock gene Period 1. PLoS Genet 17(7): e1009625. https://doi.org/10.1371/journal.pgen.1009625


Provided by PLOS

Research Reveals Structure Of Nanomachine That Assembles A Cell’s Energy Control System (Biology)

Sussex researchers have determined the structure of a tiny multi-protein biological machine, furthering our understanding of human cells and helping to enhance research into cancer, neurodegeneration and other illnesses

Researchers from the University of Sussex have determined the structure of a tiny multi-protein biological machine, furthering our understanding of human cells and helping to enhance research into cancer, neurodegeneration and other illnesses.

A biological nanomachine is a macromolecular machine commonly found within the cell, often in the form of multi-protein complexes, which frequently perform tasks essential for life.

The nanomachine R2TP-TTT acts as a molecular chaperone to assemble others in the human cell. It is especially important for constructing mTORC1 – a complicated nanomachine that regulates the cell’s energy metabolism, and which often becomes misregulated in human diseases such as cancer and diabetes.

Scientists from the School of Life Sciences at Sussex, working in collaboration with colleagues at CNIO Madrid, MRC-LMB Cambridge and the University of Leeds, used state-of-the-art cryo-electron microscopy (cryoEM) to build a detailed image of the R2TP-TTT nanomachine that shows the arrangement of all the proteins. It also reveals how the TTT proteins control the R2TP machine to allow it to hold components of mTORC1 ready for assembly.

Lead researcher, Dr. Mohinder Pal, working in the laboratories of Dr. Chris Prodromou and Professor Laurence Pearl FRS at Sussex, worked out how to make and purify all the proteins using an insect cell system, and apply them in an ultra-thin layer that could be frozen in liquid ethane to preserve their atomic structure. Images of the frozen protein particles magnified more than 50,000 times were then collected on cryo-electron microscopes in Madrid, Harwell and Leeds. These were then combined using a technology related to medical tomography, to give the final detailed image of the R2TP-TTT, in which the molecular detail could be seen and analysed.

Professor Pearl, who co-supervised the work with Dr. Prodromou and Prof. Llorca (Madrid), commented :

“Previously we’ve been able to work out the structures of protein molecules, using a technique called X-ray crystallography, but usually only individually or in pieces. The revolution in cryoEM technology over the last couple of years has given us the ability to look at the large assemblies of proteins as they actually exist in the cell, and really understand how they work as biological nanomachines.”

With the help of the RM Phillips Charitable Trust, the University of Sussex has made a multi-million pound investment to establish cryo-electron microscopy in the School of Life Sciences. The new state-of-the-art cryoARM200 cryo-electron microscope, made by the Japanese company JEOL, has just been installed in the John Maynard Smith building at the University, and will be fully functioning in the summer.

Professor Pearl said :

“Having our own instrument on site, will greatly increase the speed with which we can reveal the structures of a huge range of biological nanomachines being studied by colleagues in Life Sciences. This will massively enhance the world-leading work going on here at Sussex to understand cancer, neurodegeneration and viral diseases, and to develop new treatments”.

The work, which was funded by the Biological and Biotechnology Research Council (BBSRC) and The Welcome Trust, published in the journal Cell Reports on July 6th.

Featured image: Graphical abstract © Pal et al.


Reference: Reference: Mohinder Pal et al., “Structure of the TELO2-TTI1-TTI2 complex and its function in TOR recruitment to the R2TP chaperone”, Cell Reports, 36(1), 2021. DOI: https://doi.org/10.1016/j.celrep.2021.109317


Provided by University of Sussex

Artificial Intelligence Provides Faster Diagnosis For Debilitating Blistering Disease (Medicine)

Scientists at the University of Groningen have trained an Artificial Intelligence system to recognize a specific pattern in skin biopsies of patients with the blistering disease epidermolysis bullosa acquisita. The pattern is characteristic of a specific variant of the disease which can cause scarring of the skin and mucous membranes, and may lead to blindness. The new system is easy to use and is better than most doctors in making the diagnosis. A description of this AI system is published in The American Journal of Pathology.

In patients with epidermolysis bullosa, layers of the skin get detached, causing large blisters. There are different forms of blistering diseases affecting different layers of the skin. One of these, epidermolysis bullosa acquisita (EBA), is an autoimmune disease through which a patient’s own antibodies attack the skin. It usually starts around middle age and the blisters can form scars. Scarring on the skin may lead to limiting the movement of joints but scars can also form in mucous membranes. When this happens in the eye, for example, it may lead to blindness. Early diagnosis is required to prevent the damage caused by scarring.

Pattern

‘At the moment, it can take months to years before the diagnosis of EBA is confirmed’, explains Joost Meijer, dermatologist at the University Medical Center Groningen and joint first author of the paper. Diagnosing EBA happens through skin biopsies, where fluorescent markers attach to the autoantibodies in the basal layer of the epidermis. This produces a serrated U-shaped pattern, typical for EBA. ‘However, you need to find and recognize this pattern in a relatively large microscopic slide’, Meijer continues. The pattern may only be present in small parts of the slide. To give an idea of how small it is, if the microscopic image is digitized as a picture of 20,000 x 12,000 pixels, the pattern could only take up a 30 x 30 pixel space.

Meijer wrote his Master’s thesis on diagnostic techniques to recognize this pattern. He then went on to study the problem in his PhD research, in which he teamed up with fellow PhD student Astone Shi at the University of Groningen’s Bernoulli Institute for Mathematics, Computer Science and Artificial Intelligence. Shi, the other joint first author of the paper, works with Convoluted Neural Networks (CNNs), a type of system that works with deep learning and is particularly suited for pattern recognition.

Patients

‘One challenge was that there is no standard training program for this particular pattern’, says Shi. He had to find the best type of CNN and the best way to train it. ‘There are millions of parameters in these neural networks, and we had to find the ones that work best.’ Another problem is finding data with which to train the CNN. Patients with EBA are rare; at the moment, there are only around 5 to 10 patients diagnosed per year in the Netherlands. Meijer and Shi were able to use biopsies from 46 patients; 42 to train the networks and the remaining four to validate the system.

Astone Shi (left) and Joost Meijer | Photo's UoG/UMCG
Astone Shi (left) and Joost Meijer | Photo’s UoG/UMCG

After training nine different CNNs and repeating the procedure 10 times, the AI system was able to recognize EBA with both specificity and sensitivity equal to 89.3 percent. This is better than the numbers published by a group of pathologists and dermatologists, and just below the accuracy of a small number of highly trained specialists. Shi: ‘This means that our system outperforms most doctors.’ The reason for this is probably that the human eye only takes a relatively small portion of a microscopic slide into account. Meijer: ‘Observers get a first impression from this, and then search the slide for confirmation. The AI system analyses the entire slide, which results in a more accurate diagnosis.’

European study

The main advantage of this digital system is that it would be easy to use. Meijer: ‘We envisage a system where you upload an image and then get a diagnosis from the AI algorithm.’ However, it could also be used to train doctors in recognizing the specific U-serrated pattern of EBA. Although the system worked well in this research project, the results need to be confirmed for a new, larger dataset. For this purpose, a prospective European study has been started. Meijer: ‘It will take a year to collect the data of new skin biopsies, which will be able to validate the system. Hopefully, we will then have a quicker and easier way to diagnose EBA and prevent the sometimes debilitating scarring.’

Featured image: The U-shaped pattern (in green) visible in the skin biopsy of an EBA patient | Image UMCG/UoG.


Reference: C. Shi, J. M. Meijer, G. Azzopardi, G. F. H. Diercks, J. Guo, N. Petkov: Use of convolutional neural networks for the detection of u-serrated patterns in direct immunofluorescence images to facilitate the diagnosis of epidermolysis bullosa acquisita. American Journal of Pathology, first online 27 June 2021.


Provided by University of Groningen

Inhaled COVID-19 Vaccine Prevents Disease And Transmission in Animals (Medicine)

In a new study assessing the potential of a single-dose, intranasal COVID-19 vaccine, a team from the University of Iowa and the University of Georgia found that the vaccine fully protects mice against lethal COVID-19 infection. The vaccine also blocks animal-to-animal transmission of the virus. The findings were published July 2 in the journal Science Advances.

“The currently available vaccines against COVID-19 are very successful, but the majority of the world’s population is still unvaccinated and there is a critical need for more vaccines that are easy to use and effective at stopping disease and transmission,” says Paul McCray, MD, professor of pediatrics-pulmonary medicine, and microbiology and immunology at the UI Carver College of Medicine, and co-leader of the study. “If this new COVID-19 vaccine proves effective in people, it may help block SARS-CoV-2 transmission and help control the COVID-19 pandemic.”

Unlike traditional vaccines that require an injection, this vaccine is administered through a nasal spray similar to those commonly used to vaccinate against influenza. The vaccine used in the study only requires a single dose and it may be stored at normal refrigerator temperatures for up to at least three months. Because it is given intranasally, the vaccine may also be easier to administer, especially for those who have a fear of needles.

“We have been developing this vaccine platform for more than 20 years, and we began working on new vaccine formulations to combat COVID-19 during the early days of the pandemic,” says Biao He, PhD, a professor in the University of Georgia’s Department of Infectious Diseases in the College of Veterinary Medicine and co-leader of the study. “Our preclinical data show that this vaccine not only protects against infection, but also significantly reduces the chances of transmission.”

The experimental vaccine uses a harmless parainfluenza virus 5 (PIV5) to deliver the SARS-CoV-2 spike protein into cells where it prompts an immune response that protects against COVID-19 infection. PIV5 is related to common cold viruses and easily infects different mammals, including humans, without causing significant disease. The research team has previously shown that this vaccine platform can completely protect experimental animals from another dangerous coronavirus disease called Middle Eastern Respiratory Syndrome (MERS).

The inhaled PIV5 vaccine developed by the team targets mucosal cells that line the nasal passages and airways. These cells are the main entry point for most SARS-CoV-2 infections and the site of early virus replication. Virus produced in these cells can invade deeper into the lungs and other organs in the body, which can lead to more severe disease. In addition, virus made in these cells can be easily shed through exhalation allowing transmission from one infected person to others.

The study showed that the vaccine produced a localized immune response, involving antibodies and cellular immunity, that completely protected mice from fatal doses of SARS-CoV-2. The vaccine also prevented infection and disease in ferrets and, importantly, appeared to block transmission of COVID-19 from infected ferrets to their unprotected and uninfected cage-mates.

In addition to McCray, UI researchers involved in the study included Kun Li, PhD, an associate research scientist, who helped lead the small animal studies at Iowa, documenting the vaccine’s efficacy, and David Meyerholz, PhD, UI professor of pathology.

The research was supported by CyanVac LLC, a startup company based at University of Georgia that is developing vaccines based on the PIV5. McCray, who does not have a financial relationship with CyanVac, also received support from the Roy J. Carver Charitable Trust.


Reference: Dong An, Kun Li, Dawne K. Rowe, Maria Cristina Huertas Diaz, Emily F. Griffin, Ashley C. Beavis, Scott K. Johnson, Ian Padykula, Cheryl A. Jones, Kelsey Briggs, Geng Li, Yuan Lin, Jiachen Huang, Jarrod Mousa, Melinda Brindley, Kaori Sakamoto, David K. Meyerholz, Paul B. McCray, Jr., S. Mark Tompkins, Biao He, “Protection of K18-hACE2 mice and ferrets against SARS-CoV-2 challenge by a single-dose mucosal immunization with a parainfluenza virus 5–based COVID-19 vaccine”, Science Advances, 2021. DOI: https://doi.org/10.1126/sciadv.abi5246


Provided by Carver College of Medicine