Japanese–European Research Team Discovers Novel Genetic Mitochondrial Disorder (Biology)

Team of Japanese and European scientists identify a novel genetic mitochondrial disorder by analyzing DNA samples from three distinct families

The list of known genetic mitochondrial disorders is ever-growing, and ongoing research continues to identify new disorders in this category. In an article recently published in Brain, a Japanese-European team of scientists, including researchers from Fujita Health University, describe mutations in the LIG3 gene, which plays a crucial role in mitochondrial DNA replication. These mutations cause a previously unknown syndrome characterized by gut dysmotility, leukoencephalopathy, and neuromuscular abnormalities.

DNA ligase proteins, which facilitate the formation of bonds between separate strands of DNA, play critical roles in the replication and maintenance of DNA. The human genome encodes three different DNA ligase proteins, but only one of those proteins—DNA ligase III (LIG3)—is expressed in mitochondria. LIG3 is therefore crucial for mitochondrial health, and inactivation of the homologous protein in mice causes profound mitochondrial dysfunction and early embryonic mortality. In an article recently published in the peer-reviewed journal Brain, a team of European and Japanese scientists, led by Dr. Mariko Taniguchi-Ikeda from Fujita Health University Hospital, describes a set of seven patients with a novel mitochondrial disorder caused by biallelic variants in the gene that encodes the LIG3 protein, called the “LIG3” gene. Their report provides a description of the patients’ symptoms and a mechanistic exploration of the mutations’ effects.

For Dr. Taniguchi-Ikeda, the investigation began with her desire to help a young patient. “I wanted to make a distinct clinical and genetic diagnosis for the affected patient,” she explains, “because his elder brother had passed away and the surviving boy was referred to my outpatient ward for detailed genetic tests.” By performing whole-exome sequencing of DNA from the surviving patient, Dr. Taniguchi-Ikeda discovered that he had inherited a p.P609L LIG3 variant from his father and a p.R811Ter LIG3 variant from his mother. The parents had kept the deceased brother’s dried umbilical cord, and by analyzing DNA extracted from that source, Dr. Taniguchi-Ikeda confirmed that the brother had carried the same LIG3 variants.

Having detected a novel genetic mitochondrial disorder, Dr. Taniguchi-Ikeda wished to conduct further research by identifying other patients with pathogenic LIG3 variants. She could find no other such cases in Japan, but through a collaboration with Dr. Makiko Tsutsumi from Fujita Health University and researchers in Europe, including Professor Elena Bonora from the University of Bologna and Professor Roberto De Giorgio from the University of Ferrara, she learned of two European families also affected by such variants. One was an Italian family in which three brothers had all inherited a p.K537N variant from their father and a p.G964R variant from their mother, and the other was a Dutch family in which two daughters had inherited a p.R267Ter variant from their father and a p.C999Y variant from their mother.

These patients experienced a complex syndrome involving severe gut dysmotility and neurologic abnormalities as the most consistently observed clinical signs. The neurologic abnormalities included leukoencephalopathy, epilepsy, migraine, stroke-like episodes, and neurogenic bladder. The prominent changes in the gut were decreased myenteric neuron counts and elevated fibrosis and elastin levels. Muscle pathology assessments revealed decreased staining intensities for cytochrome C oxidase.

To better characterize how the patients’ LIG3 mutations could lead to such phenotypes, the researchers conducted experiments both in vitro and on zebrafish. The in vitro experiments with patient-derived fibroblasts showed that the mutations resulted in reduced LIG3 protein levels and diminished ligase activity. The consequent deficits in mitochondrial DNA maintenance would do much to explain the patients’ presentations. Experiments with zebrafish showed that disrupting the lig3 gene produced brain alterations and gut transit impairments analogous to those observed in the patients.

The study brings to light a novel disorder resulting from disruption of a gene that plays a critical role in the maintenance of mitochondrial DNA. In describing the importance of these findings, Dr. Taniguchi-Ikeda concludes, “Our study may facilitate efforts to diagnose patients with mitochondrial diseases. Our findings will also be beneficial to future investigations into the mitochondrial DNA repair system.”

Featured image: A Japanese-European team of scientists described novel mutations in the LIG3 gene, which plays a key role in mitochondrial DNA replication. Normally, mitochondrial DNA is repaired and replicated by LIG3 activity, but if the gene contains mutations, enzymes necessary for energy production are not produced, potentially leading to central nervous system symptoms and muscle defects. © FHU

Reference: Elena Bonora, Sanjiban Chakrabarty, Georgios Kellaris, Makiko Tsutsumi, Francesca Bianco, Christian Bergamini, Farid Ullah, Federica Isidori, Irene Liparulo, Chiara Diquigiovanni, Luca Masin, Nicola Rizzardi, Mariapia Giuditta Cratere, Elisa Boschetti, Valentina Papa, Alessandra Maresca, Giovanna Cenacchi, Rita Casadio, Pierluigi Martelli, Ivana Matera, Isabella Ceccherini, Romana Fato, Giuseppe Raiola, Serena Arrigo, Sara Signa, Angela Rita Sementa, Mariasavina Severino, Pasquale Striano, Chiara Fiorillo, Tsuyoshi Goto, Shumpei Uchino, Yoshinobu Oyazato, Hisayoshi Nakamura, Sushil K Mishra, Yu-Sheng Yeh, Takema Kato, Kandai Nozu, Jantima Tanboon, Ichiro Morioka, Ichizo Nishino, Tatsushi Toda, Yu-ichi Goto, Akira Ohtake, Kenjiro Kosaki, Yoshiki Yamaguchi, Ikuya Nonaka, Kazumoto Iijima, Masakazu Mimaki, Hiroki Kurahashi, Anja Raams, Alyson MacInnes, Mariel Alders, Marc Engelen, Gabor Linthorst, Tom de Koning, Wilfred den Dunnen, Gerard Dijkstra, Karin van Spaendonck, Dik C van Gent, Eleonora M Aronica, Paolo Picco, Valerio Carelli, Marco Seri, Nicholas Katsanis, Floor A M Duijkers, Mariko Taniguchi-Ikeda, Roberto De Giorgio, Biallelic variants in LIG3 cause a novel mitochondrial neurogastrointestinal encephalomyopathy, Brain, 2021;, awab056, https://doi.org/10.1093/brain/awab056

Provided by Fujita Health University

Understanding the Growth Of Disease-causing Protein Fibres (Chemistry)

Researchers have developed a method to directly measure the growth rate of ‘amyloid’ fibrils linked to Parkinson’s and other diseases.

Amyloid fibrils are deposits of proteins in the body that join together to form microscopic fibres. Their formation has been linked to many serious human diseases including Alzheimer’s, Parkinson’s and Type 2 diabetes.

Until today, scientists have been unable to reliably measure the speed of fibril growth, as there have been no tools that could directly measure growth rate in solution. However, researchers from the University of Bath and the ISIS Neutron and Muon Source have now invented a technique that does just that. Results from their study are published in RSC Chemical Biology.

“This is an important breakthrough, as information on fibre growth is key to understanding the diseases associated with amyloid fibrils,” said Dr Adam Squires from the Department of Chemistry at Bath, and study co-author. “Knowing what makes these fibres grow faster or slower, or whether they break and what makes them break – in other words, understanding these fibres at a molecular level – could eventually have implications for researchers looking for treatments for these serious diseases.”

He added: “This new technique will also help scientists investigating non-medical roles of protein folding and self-assembly – for instance, in biological processes such as inheritance in yeast, or for research into new nanomaterials.”

Why growth rate is best measured in solution

Most experimental techniques for measuring fibril growth in solution only measure how fast proteins transform into fibril material overall, not how long each fibril is or how fast it is growing. Other techniques measure just one fibril attached to a surface such as glass or mica. These conditions do not reflect the real biological process, which occurs in solution.

Researchers for this new study used Small Angle Neutron Scattering (SANS) to study the growth rate and length of amyloid fibrils as they assembled. By using the unique ways neutrons interact with hydrogen and its isotope deuterium, the researchers were able to use ‘contrast matching’ to make all of the fibrils invisible to neutrons apart from the growing tips. Using the SANS2D instrument at the ISIS neutron facility, they watched these tips become longer in real time. This gave a direct measurement of the growth rate, which had never been done before.

The results of growth rate from this study align with values estimated from other methods, indicating that SANS is a suitable tool for measuring amyloid fibril growth.

The technique also allowed the researchers to measure the number of fibril ends present in a given sample. This information told them how many separate fibres were growing, and the length of each one. The fragility of fibrils from different proteins, and how often they break into shorter fragments exposing more growing ends, is a key part of the puzzle to understand fibril disease propagation.

Lead researcher Dr Ben Eves carried out the experiments at Bath as part of his ISIS Facility Development studentship.

“I’m thrilled with the success of this method,” he said. “Developing this technique was a truly amazing experience. Understanding the growth of amyloid fibrils is fundamental to understanding their pathogenic, biological and technological properties.”

He added: “In future, I believe this technique could be used to investigate the effect of different factors that affect the growth rate of amyloid fibrils, as well as to measure the impact of therapeutic molecules (the building blocks of medicines) designed to slow down or prevent the growth of amyloid fibrils.”

Featured image: Transmission Electron Micrograph of fibrils from the protein alpha-synuclein, which is associated with Parkinson’s disease. © University of Bath

Reference: Ben Jonathon Eves et al., “Elongation rate and average length of amyloid fibrils in solution using isotope-labelled small-angle neutron scattering”, RSC Chemical Biology, 2021. Link to paper

Provided by University of Bath

Investigating Heavy Quark Physics With the LHCb Experiment (Physics)

In ten years of operation the LHCb experiment has probed the nature of physics attempting to answer some of the Universe’s most fundamental questions. A new review examines its past achievements and future potential.

A new review published in EPJ H by Clara Matteuzzi, Research Director at the National Institute for Nuclear Physics (INFN) and former tenured professor at the University of Milan, and her colleagues, examines almost three decades of the LHCb experiment – from its conception to operation at the Large Hadron Collider (LHC) – documenting its achievements and future potential.

The LCHb experiment was originally conceived to understand the symmetry between matter and antimatter and where this symmetry is broken  –  known as charge conjugation parity (CP) violation. Whilst this may seem like quite an obscure area of study, it addresses one of the Universe’s most fundamental questions: how it came to be dominated by matter when it should have equally favoured antimatter?

“LHCb wants to study by which mechanism our universe, as we see it today, is made of matter, and how antimatter disappeared despite an initial symmetry between the two states,” says Matteuzzi. “The Standard Model contains a tiny amount of violation of this symmetry, whilst the observation of the universe implies a much larger one. This is one of the most fascinating open questions in the Particle Physics field.”

The LHCb experiment investigates this problem by studying the behaviour of systems and particles made from so-called heavy quarks. These are produced in abundance by highly energetic collisions  – explaining why the LHC is the perfect location to study them  – and were also abundant in the highly energetic early Universe.

“The field in which the LHCb is active is so-called ‘heavy quarks physics’ which aims to study and understand the behaviour of the particles containing the c and b heavy quarks – usually named charm and beauty quarks,” says Matteuzzi. “The rich sector  – spectroscopy  – covered by LHCb is how quarks of different types, or flavours, aggregate together to form particles in a way that is analogous to how  ‘Up’ and ‘Down’ quarks  in different combinations make protons and neutrons.”

“It became clear that the potentiality of the LHCb detector was in other fields beyond the study of CP violation that also hinged on aspects of heavy quark interaction. One was the spectacular success of spectroscopy and the measurement of many new states composed by heavy quarks,” concludes Matteuzzi. “This incredibly rich variety of results is demonstrated in our paper  –  we hope!”

References:  Belyaev I., Carboni G., Harnew N., Matteuzzi C., Teubert F. (2021), The History of LCHb, European Physical Journal H 46, 3 (2021). https://doi.org/10.1140/epjh/s13129-021-00002-z

Provided by Springer

New NASA Visualization Probes the Light-bending Dance of Binary Black Holes (Planetary Science)

A pair of orbiting black holes millions of times the Sun’s mass perform a hypnotic pas de deux in a new NASA visualization. The movie traces how the black holes distort and redirect light emanating from the maelstrom of hot gas – called an accretion disk – that surrounds each one.   

Viewed from near the orbital plane, each accretion disk takes on a characteristic double-humped look. But as one passes in front of the other, the gravity of the foreground black hole transforms its partner into a rapidly changing sequence of arcs. These distortions play out as light from both disks navigates the tangled fabric of space and time near the black holes.

Video: Explore how the extreme gravity of two orbiting supermassive black holes distorts our view. In this visualization, disks of bright, hot, churning gas encircle both black holes, shown in red and blue to better track the light source. The red disk orbits the larger black hole, which weighs 200 million times the mass of our Sun, while its smaller blue companion weighs half as much. Zooming into each black hole reveals multiple, increasingly warped images of its partner. Watch to learn more. Credit: NASA’s Goddard Space Flight Center/Jeremy Schnittman and Brian P. Powell

“We’re seeing two supermassive black holes, a larger one with 200 million solar masses and a smaller companion weighing half as much,” said Jeremy Schnittman, an astrophysicist at NASA’s Goddard Space Flight Center in Greenbelt, Maryland, who created the visualization. “These are the kinds of black hole binary systems where we think both members could maintain accretion disks lasting millions of years.”  

The accretion disks have different colors, red and blue, to make it easier to track the light sources, but the choice also reflects reality. Hotter gas gives off light closer to the blue end of the spectrum, and material orbiting smaller black holes experiences stronger gravitational effects that produce higher temperatures. For these masses, both accretion disks would actually emit most of their light in the UV, with the blue disk reaching a slightly higher temperature.

Visualizations like this help scientists picture the fascinating consequences of extreme gravity’s funhouse mirror. The new video doubles down on an earlier one Schnittman produced showing a solitary black hole from various angles.

Seen nearly edgewise, the accretion disks look noticeably brighter on one side. Gravitational distortion alters the paths of light coming from different parts of the disks, producing the warped image. The rapid motion of gas near the black hole modifies the disk’s luminosity through a phenomenon called Doppler boosting – an effect of Einstein’s relativity theory that brightens the side rotating toward the viewer and dims the side spinning away.

The visualization also shows a more subtle phenomenon called relativistic aberration. The black holes appear smaller as they approach the viewer and larger when moving away.

These effects disappear when viewing the system from above, but new features emerge. Both black holes produce small images of their partners that circle around them each orbit. Looking closer, it’s clear that these images are actually edge-on views. To produce them, light from the black holes must be redirected by 90 degrees, which means we’re observing the black holes from two different perspectives – face on and edge on – at the same time.

A face-on view of the system highlights the smaller black hole’s distorted image (inset) of its bigger companion. To reach the camera, the smaller black hole must bend light from its red companion by 90 degrees. The accretion disk of this secondary image appears as a line, which means we’re seeing an edge-on view of the red companion – while also simultaneously seeing it from above. A secondary image of the blue disk also forms just outside the bright ring of light nearest the larger black hole, too. Credits: NASA’s Goddard Space Flight Center/Jeremy Schnittman and Brian P. Powell

“A striking aspect of this new visualization is the self-similar nature of the images produced by gravitational lensing,” Schnittman explained. “Zooming into each black hole reveals multiple, increasingly distorted images of its partner.”

Schnittman created the visualization by computing the path taken by light rays from the accretion disks as they made their way through the warped space-time around the black holes. On a modern desktop computer, the calculations needed to make the movie frames would have taken about a decade. So Schnittman teamed up with Goddard data scientist Brian P. Powell to use the Discover supercomputer at the NASA Center for Climate Simulation. Using just 2% of Discover’s 129,000 processors, these computations took about a day.

Astronomers expect that, in the not-too-distant future, they’ll be able to detect gravitational waves – ripples in space-time – produced when two supermassive black holes in a system much like the one Schnittman depicted spiral together and merge.

Banner: In this frame from the new visualization, a supermassive black hole weighing 200 million solar masses lies in the foreground. Its gravity distorts light from the accretion disk of a smaller companion black hole almost directly behind it, creating this surreal view. Different colors for the accretion disks make it easier to track the contributions of each one. Credit: NASA’s Goddard Space Flight Center/Jeremy Schnittman and Brian P. Powell

Provided by NASA/Goddard

A Neuromagnetic View Through The Skull (Neuroscience)

First noninvasive measurements of fast brain signals

The processing of information inside the brain is one of the body’s most complex processes. Disruption of this processing often leads to severe neurological disorders. The study of signal transmission inside the brain is therefore key to understanding a myriad of diseases. From a methodological point of view, however, it creates major challenges for researchers. The desire to observe the brain’s nerve cells operating ‘at the speed of thought’, but without the need to place electrodes inside the brain, has led to the emergence of two techniques featuring high temporal resolution: electroencephalography (EEG) and magnetoencephalography (MEG). Both methods enable the visualization of brain activity from outside the skull. However, while results for slow currents are reliable, those for fast currents are not.

Slow currents – known as postsynaptic potentials – occur when signals created by one nerve cell are received by another. The subsequent firing of impulses (which transmit information to downstream neurons or muscles) produces fast currents which last for just a millisecond. These are known as action potentials. “Until now, we have only been able to observe nerve cells as they receive information, not as they transmit information in response to a single sensory stimulus,” explains Dr. Gunnar Waterstraat of Charité’s Department of Neurology with Experimental Neurology on Campus Benjamin Franklin. “One could say that we were effectively blind in one eye.” Working under the leadership of Dr. Waterstraat and Dr. Rainer Körber from the PTB, a team of researchers has now laid the foundations which are needed to change this. The interdisciplinary research group succeeded in rendering the MEG technology so sensitive as to enable it to detect even fast brain oscillations produced in response to a single sensory stimulus.

They did this by significantly reducing the system noise produced by the MEG device itself. “The magnetic field sensors inside the MEG device are submerged in liquid helium, to cool them to -269°C (4.2 K),” explains Dr. Körber. He adds: “To do this, the cooling system requires complex thermal insulation. This superinsulation consists of aluminum-coated foils which produce magnetic noise and will therefore mask small magnetic fields such as those associated with nerve cells. We have now changed the design of the superinsulation in such a way as to ensure this noise is no longer measurable. By doing this, we managed to increase the MEG technology’s sensitivity by a factor of ten.”

The researchers used the example of stimulating a nerve in the arm to demonstrate that the new device is indeed capable of recording fast brain waves. As part of their study on four healthy subjects, the researchers applied electrical stimulation to a specific nerve at the wrist whilst at the same time positioning the MEG sensor immediately above the area of the brain which is responsible for processing sensory stimuli applied to the hand. To eliminate outside sources of interference such as electric networks and electronic components, the measurements were conducted in one of the PTB’s shielded recording rooms. The researchers found that, by doing so, they were able to measure the action potentials produced by a small group of simultaneously activated neurons in the brain’s cortex in response to individual stimuli. “For the first time, a noninvasive approach enabled us to observe nerve cells in the brain sending information in response to a single sensory stimulus,” says Dr. Waterstraat. He continues: “One interesting observation was the fact that these fast brain oscillations are not uniform in nature but change with each stimulus. These changes also occurred independently of the slow brain signals. There is enormous variability in how the brain processes information about the touch of a hand, despite all of the stimuli applied being identical.”

The fact that the researchers are now able to compare individual responses to stimuli opens the way for neurology researchers to investigate questions which previously remained unanswered: To what extent do factors such as alertness and tiredness influence the processing of information in the brain? What about additional stimuli which are received at the same time? The highly sensitive MEG system could also help scientists to develop a deeper understanding of, and better treatments for, neurological disorders. Epilepsy and Parkinson’s disease are examples of disorders which are linked to disruptions in fast brain signaling. “Thanks to this optimized MEG technology, our neuroscience toolbox has gained a crucial new tool which enables us to address all of these questions noninvasively,” says Dr. Waterstraat.


Like all other electrical currents, brain activity generates magnetic fields. The brain’s magnetic field, however, is approximately one billion times weaker than the Earth’s magnetic field and measures at just a few femtotesla. Magnetoencephalography is used to measure the neuromagnetic signals produced when the brain’s electrical impulses move inside or between cells. Measuring the brain’s magnetic field in this manner requires the use of superconducting quantum interference devices – or SQUID sensors.

Featured image: For the first time, researchers were able to demonstrate that noninvasively measured fast brain oscillations show significant variability from stimulus to stimulus (rows), both in terms of the timing of successive action potentials (shifts in blue/red vertical bands) and in terms of their strength (color intensity). © Charité | Gunnar Waterstraat

Reference: Gunnar Waterstraat, Rainer Körber, Jan-Hendrik Storm, Gabriel Curio, “Noninvasive neuromagnetic single-trial analysis of human neocortical population spikes”, Proceedings of the National Academy of Sciences Mar 2021, 118 (11) e2017401118; DOI: 10.1073/pnas.2017401118

Provided by PTB

Lung Cancer Screening Predicts Risk of Death from Heart Disease (Medicine)

At A Glance

  • A deep learning algorithm accurately predicts the risk of death from cardiovascular disease using information from lung cancer screening CT exams.
  • Data from 4,451 participants in the National Lung Screening Trial was used to train the algorithm to quantify six types of vascular calcification.
  • Cardiovascular disease is the leading cause of mortality worldwide. It outpaces lung cancer as the leading cause of death in heavy smokers.

A deep learning algorithm accurately predicts the risk of death from cardiovascular disease using information from low-dose CT exams performed for lung cancer screening, according to a study published in Radiology: Cardiothoracic Imaging.

Cardiovascular disease is the leading cause of mortality worldwide. It even outpaces lung cancer as the leading cause of death in heavy smokers.

Low-dose CT lung scans are used to screen for lung cancer in high-risk people such as heavy smokers. These CT scans also provide an opportunity to screen for cardiovascular disease by extracting information about calcification in the heart and aorta. The presence of calcium in these areas is linked with the buildup of plaque and is a strong predictor for cardiovascular disease mortality, heart attacks and strokes.

Previous studies have used information extracted from CT images as well as other risk factors, such as cholesterol levels and blood pressure, and self-reported clinical data, such as history of illness.

Bob D. de Vos, Ph.D. © RSNA

For the new study, researchers tested a faster, automated method that can predict five-year cardiovascular disease mortality with only minimal extra workload. The method draws upon the power of deep learning, an advanced type of artificial intelligence in which the computer algorithm essentially learns from the images the important features for mortality prediction.

Using data from 4,451 participants, median age 61 years, who underwent low-dose CT over a two-year period in the National Lung Screening Trial, the researchers trained the method to quantify six types of vascular calcification. They then tested the method on data from 1,113 participants.

The prediction model using calcium scores outperformed the baseline model that used only self-reported participant characteristics, such as age, history of smoking, and history of illness.

The method works in two stages, according to study lead author Bob D. de Vos, Ph.D., from Amsterdam University Medical Center in Amsterdam and the Image Sciences Institute, University Medical Center Utrecht, in Utrecht, the Netherlands. The first stage determines the amount and location of arterial calcification in the coronary arteries and the aorta using deep learning. The second stage uses a more conventional statistical approach for mortality prediction. The second stage also indicates which features are most predictive for five-year mortality.

Figure 2. Projections of all aligned chest CT scans show feasibility of slab-based quantification of calcium, resulting in an average image. For alignment, only translation, rotation, and scaling were allowed, resulting in a blurry image, because not all anatomy is exactly the same across participants. From left to right, the center axial, sagittal, and coronal sections are shown. Note that field of view is similar to cardiac CT, which is a consequence of image alignment by the used automatic calcium scoring method. Image alignment allowed the determination of calcification distributions into slabs as a proxy measure for proximal and distal calcifications, of which the borders are indicated by the horizontal lines. © RSNA

“The analysis shows we found predictors that are typically not described in a literature, possibly because we performed analysis in lung cancer screening participants who are already at high risk of cardiovascular disease from a history of heavy smoking and the presence of extensive arterial calcification,” Dr. de Vos said.

The method could easily be integrated into lung cancer screening, Dr. de Vos said. It does not require any special equipment and would not add time to the exam.

“The method uses only image information, it is fully automatic, and it is fast,” Dr. de Vos said. “The method obtains calcium scores in a complete chest CT in less than half a second. This means that the method should be easy to implement in routine patient work ups and screening.”

Figure 3. Full pipeline from input to output. xn = resulting calcium scores. LASSO = least absolute shrinkage and selection operator. © RSNA

Most importantly, the method could help identify people in a population of heavy smokers who might be at increased risk of death from cardiovascular disease-related causes.

“Lung screening studies show that heavy smokers die from cardiovascular disease as much as from lung cancer,” Dr. de Vos said. “But we also see that some people with very high calcium scores survive, while others with low scores do suffer from major cardiac events. The work offers a direction for future research to precisely pinpoint which calcifications are dangerous.”

The researchers have developed a number of methods for automatic calcium scoring that can be applied to a wide variety of data. They are now working toward a calcium scoring method that accurately detects arterial calcification in low-quality data, like data affected by cardiac motion, low image resolution or high noise levels.

“We developed a method, for example, that can detect coronary calcifications even when the lesions are below the clinically used threshold,” Dr. de Vos said. “This way, we hope to increase the reproducibility of calcium scoring and enable more accurate prediction.”

The United States Preventive Services Task Force (USPSTF) recently expanded its recommendation for low-dose CT lung cancer screening to include high-risk individuals, 50 to 80 years of age, who have a 20-pack-year or more history of smoking and are either current smokers or former smokers who have quit within the last 15 years, facilitating screening access for a larger and more diverse population. Read more in RSNA News.

Featured image: Feature importance of the derived model using only location-specific calcium scores as image features. Feature importance is determined by scaling the coefficients obtained by least absolute shrinkage and selection operator regression. For reference, the average coronal center section of all aligned chest CT scans is shown. LAD = left anterior descending artery, LCX = left circumflex artery, LM = left main, RCA = right coronary artery. © RSNA

Provided by RSNA

New Type of Cell Contributes To Increased Understanding of ALS (Medicine)

The causes of the serious muscle disease ALS still remain unknown. Now, researchers at Karolinska Institutet and KTH Royal Institute of Technology, among others, have examined a type of cell in the brain blood vessels that could explain the unpredictable disease origins and dynamics. The results indicate a hitherto unknown connection between the nervous and vascular systems. The study, which is published in Nature Medicine, has potential implications for earlier diagnoses and future treatments.

ALS (amyotrophic lateral sclerosis) is a neurodegenerative disease of the motor neurons that eventually causes muscular atrophy, paralysis and death. There is currently no cure.

The cause of ALS is only understood in the 5 to 10 per cent of patients who have an inherited form of the disease. To help in its early detection and to develop efficacious therapies, researchers are avidly seeking a clearer picture of the disease’s pathogenesis.

ALS patients demonstrate high variability of age at onset, non-motor symptoms and survival. In recent years, research has shifted focus from neurological explanations to these differences, and has taken an interest, for example, in the cerebral vascular system, which delivers oxygen and nutrients to brain tissue.

Anna Månberg, researcher at the Department of Protein Science, at KTH Royal Institute of Technology and SciLifeLab. © KTH Royal Institute of Technology

Researchers at Karolinska Institutet, KTH Royal Institute of Technology, SciLifeLab, London’s Imperial College and Umeå University have now studied whether a possible connection exists between perivascular fibroblast cells and the time of disease onset and survival.

Studies on mice with ALS showed that genes for perivascular fibroblasts were active already in an early asymptomatic stage of the disease and months before neuronal damage began to appear.

The researchers then examined the levels of a large number of potential marker proteins in the plasma of 574 patients with a recent ALS diagnosis and 504 healthy controls from four countries.

Their results suggest a correlation between elevated levels of the protein marker SPP1 for perivascular fibroblasts and an aggressive disease process and shorter survival. This is the first time a connection between the vascular and nervous systems in sporadic ALS has been observed.

“It is exciting to see how the results from our protein profiling could be connected to the long range of cellular and molecular analysis that we have done and reveal the identified association to disease progression,” says the first author Anna Månberg, researcher at the Department of Protein Science, at KTH and SciLifeLab.

“Our results indicate that vascular events are a factor in the disease’s heterogeneity and can improve our knowledge of early stage ALS,” says the study’s last and senior author Sebastian Lewandowski, researcher at the Department of Clinical Neuroscience and the Centre for Molecular Medicine at Karolinska Institutet. “More studies are now needed on vascular disease mechanisms for better prognostic tools and future treatments.”

The research was financed by the Olle Engkvist Foundation, the Ulla-Carin Lindquist Foundation for ALS Research, the Swedish FTD Initiative and others, and received strategic support from the Knut and Alice Wallenberg Foundation and the Erling-Persson Family Foundation for the KTH Center for Applied Precision Medicine (KCAP). See the paper for further details of the researchers’ other work.

Featured image: Sebastian Lewandowski, researcher at the Department of Clinical Neuroscience, Karolinska Institutet. © Ulf Sirborn

Publication: “Altered perivascular fibroblast activity precedes ALS disease onset”, Anna Månberg, Nathan Skene, Folkert Sanders, Marta Trusohamn, Julia Remnestål, Anna Szczepi?ska, Inci Sevval Aksoylu, Peter Lönnerberg, Lwaki Ebarasi, Stefan Wouters, Manuela Lehmann, Jennie Olofsson, Inti Von Gohren Antequera, Aylin Domaniku, Maxim De Schaepdryver, Joke De Vocht, Koen Poesen, Mathias Uhlén, Jasper Anink, Caroline Mijnsbergen, Hermieneke Vergunst-Bosch, Annemarie Hübers, Ulf Kläppe, Elena Rodriguez-Vieitez, Jonathan D. Gilthorpe, Eva Hedlund, Robert A. Harris, Eleonora Aronica, Philip Van Damme, Albert Ludolph, Jan Veldink, Caroline Ingre, Peter Nilsson, Sebastian A. Lewandowski. Nature Medicine, online 15 April 2021, doi: 10.1038/s41591-021-01295-9.

Provided by Karolinska Institute

Baked Meteorites Yield Clues to Planetary Atmospheres (Planetary Science)

The gases released from meteorite samples heated in a high-temperature furnace can tell scientists about the initial composition of the atmospheres of rocky exoplanets

In a novel laboratory investigation of the initial atmospheres of Earth-like rocky planets, researchers at UC Santa Cruz heated pristine meteorite samples in a high-temperature furnace and analyzed the gases released.

Their results, published April 15 in Nature Astronomy, suggest that the initial atmospheres of terrestrial planets may differ significantly from many of the common assumptions used in theoretical models of planetary atmospheres.

“This information will be important when we start being able to observe exoplanet atmospheres with new telescopes and advanced instrumentation,” said first author Maggie Thompson, a graduate student in astronomy and astrophysics at UC Santa Cruz.

The early atmospheres of rocky planets are thought to form mostly from gases released from the surface of the planet as a result of the intense heating during the accretion of planetary building blocks and later volcanic activity early in the planet’s development.

“When the building blocks of a planet are coming together, the material is heated and gases are produced, and if the planet is large enough the gases will be retained as an atmosphere,” explained coauthor Myriam Telus, assistant professor of Earth and planetary sciences at UC Santa Cruz. “We’re trying to simulate in the laboratory this very early process when a planet’s atmosphere is forming so we can put some experimental constraints on that story.”

The researchers analyzed three meteorites of a type known as CM-type carbonaceous chondrites, which have a composition considered representative of the material from which the sun and planets formed.

“These meteorites are left over materials from the building blocks that went into forming the planets in our solar system,” Thompson said. “Chondrites are different from other types of meteorites in that they didn’t get hot enough to melt, so they have held onto some of the more primitive components that can tell us about the composition of the solar system around the time of planet formation.”

Samples from three carbonaceous chondrite meteorites–Murchison, Jbilet Winselwan, and Aguas Zarcas–were analyzed in the outgassing experiments. Image courtesy of M. Thompson

Working with materials scientists in the physics department, the researchers set up a furnace connected to a mass spectrometer and a vacuum system. As the meteorite samples were heated to 1200 degrees Celsius, the system analyzed the volatile gases produced from the minerals in the sample. Water vapor was the dominant gas, with significant amounts of carbon monoxide and carbon dioxide, and smaller amounts of hydrogen and hydrogen sulfide gases also released.

According to Telus, models of planetary atmospheres often assume solar abundances–that is, a composition similar to the sun and therefore dominated by hydrogen and helium.

“Based on outgassing from meteorites, however, you would expect water vapor to be the dominant gas, followed by carbon monoxide and carbon dioxide,” she said. “Using solar abundances is fine for large, Jupiter-size planets that acquire their atmospheres from the solar nebula, but smaller planets are thought to get their atmospheres more from outgassing.”

Assistant Professor Myriam Telus and graduate student Maggie Thompson in the lab where they performed meteorite outgassing experiments. (Photo by Jeremy Colvin)

The researchers compared their results with the predictions from chemical equilibrium models based on the composition of the meteorites. “Qualitatively, we get pretty similar results to what the chemical equilibrium models predict should be outgassed, but there are also some differences,” Thompson said. “You need experiments to see what actually happens in practice. We want to do this for a wide variety of meteorites to provide better constraints for the theoretical models of exoplanetary atmospheres.”

Other researchers have done heating experiments with meteorites, but those studies were for other purposes and used different methods. “A lot of people are interested in what happens when meteorites enter Earth’s atmosphere, so those kinds of studies were not done with this framework in mind to understand outgassing,” Thompson said.

The three meteorites analyzed for this study were the Murchison chondrite, which fell in Australia in 1969; Jbilet Winselwan, collected in Western Sahara in 2013; and Aguas Zarcas, which fell in Costa Rica in 2019.

“It may seem arbitrary to use meteorites from our solar system to understand exoplanets around other stars, but studies of other stars are finding that this type of material is actually pretty common around other stars,” Telus noted.

The investigation brought together researchers from three departments at UCSC: Astronomy and Astrophysics, Earth and Planetary Sciences, and Physics. In addition to Thompson and Telus, the coauthors of the paper include astrophysicist Jonathan Fortney and physicists Toyanath Joshi and David Lederman at UC Santa Cruz, and Laura Schaefer at Stanford University. This research was supported by NASA and the ARCS Foundation.

Featured image: The early atmospheres of rocky planets are thought to form mostly from gases released from the surface of the planet as a result of the intense heating during the accretion of planetary building blocks and later volcanic activity early in the planet’s development. © Illustration by Dan Durda/Southwest Research Institute

Provided by University of California Santa Cruz

Norovirus Clusters Are Resistant to Environmental Stresses and UV Disinfection, New Study Finds (Medicine)

Findings suggest need to reconsider current disinfection, sanitation and hygiene practices

Clusters of a virus known to cause stomach flu are resistant to detergent and ultraviolet disinfection, according to new research co-led by Danmeng Shuai, Ph.D., an associate professor of civil and environmental engineering at the George Washington University and Nihal Altan-Bonnet, Ph.D., a senior investigator and the head of the Laboratory of Host-Pathogen Dynamics at the National Heart, Lung, and Blood Institute, part of the National Institutes of Health. The findings suggest the need to revisit current disinfection, sanitation and hygiene practices aimed at protecting people from noroviruses.

Noroviruses are the leading cause of gastroenteritis around the world, with over 21 million cases each year in the United States alone.

In 2018, Altan-Bonnet’s team found that noroviruses can be transmitted to humans via membrane-enclosed packets that contain more than one virus. In the past, scientists thought that viruses spread through exposure to individual virus particles, but the 2018 study–and others–showed how membrane-enclosed clusters arrive at a human cell and release an army of viruses all at once.

For the new study, Shuai, Altan-Bonnet and the study’s first author Mengyang Zhang, a doctoral student co-advised through a GW/NIH Graduate Partnerships Program, looked at the behavior of these protected virus clusters in the environment. They found that the virus clusters could survive attempts to disinfect with detergent solutions or even UV light. Water treatment plants use UV light to kill noroviruses and other pathogens.

“These membrane-cloaked viruses are tricky,” Shuai said. “Past research shows they can evade the body’s immune system and that they are highly infectious. Our study shows these membrane enclosed viruses are also able to dodge efforts to kill them with standard disinfectants.”

Altan-Bonnet added, “We have to consider these viral clusters cloaked in vesicle membranes as unique infectious agents in the public health arena. When it comes to virulence — and now with this study, disinfection and sanitation — the sum is much more than its parts. And these clusters are endowed with properties that are absent from other types of viral particles.”

According to the researchers, future studies must be done to find out if certain kinds of cleaning solutions or higher dosages of UV light would degrade the protective membrane and/or kill the viruses inside. Ultimately, the research could be used to devise more effective disinfection methods that could be used to clean surfaces at home, in restaurants and in places where norovirus can spread and cause outbreaks, like cruise ships.

“Our study’s findings represent a step towards recommendations for pathogen control in the environment, and public health protection,” Altan-Bonnet said.

The study, “Emerging Pathogenic Unit of Vesicle-Cloaked Murine Norovirus Clusters is Resistant to Environmental Stresses and UV254 Disinfection,” will appear online in the journal Environmental Science & Technology on April 15, 2021. This work was supported by the National Science Foundation (CBET-2028464), the National Heart, Lung, and Blood Institute, and National Institute of Allergy and Infectious Diseases Intramural Research Programs.

Featured image: Vesicles containing clusters of viruses, including norovirus, within the gut. © NIH

Provided by George Washington University