ARE WE NOT MEN? NO! WE ARE MICE!

From grave to cradle: Collagen-induced gut cell reprogramming

Peer-Reviewed Publication

TOKYO MEDICAL AND DENTAL UNIVERSITY

 

IMAGE: A SIMPLIFIED PRESENTATION OF EPITHELIAL PLASTICITY SHOWING HOW COLLAGEN TYPE I INITIATES CHANGES THE EPITHELIAL IDENTITY view more 

CREDIT: CENTER FOR STEM CELL AND REGENERATIVE MEDICINE, TMDU

Researchers from Tokyo Medical and Dental University (TMDU) find that collagen deposition at sites of intestinal injury activates inflammatory and regenerative signaling in both mouse and human cells

 

Tokyo, Japan – Most cells have a pretty normal life: they’re born, they grow, they get old, and they die. But the Benjamin Buttons of the cellular world can go from old to young again in the right context. Now, researchers from Japan have identified a physical cue that sparks this change in cells in the human gut.

 

In a study published this month in Inflammation and Regeneration, researchers from Tokyo Medical and Dental University (TMDU) have revealed that the accumulation of a thick, extracellular material called collagen at injured sites in the gut stimulates cellular reprogramming.

 

When the intestine is injured, an inflammatory response occurs that is often associated with regeneration of the injured tissues. This process involves converting some mature intestinal cells back into fetal-like cells that can then generate new healthy tissue to repair the injured area.

 

“We previously showed that deposition of collagen at the site of intestinal injury promotes the conversion of intestinal/colonic epithelial cells covering the wound bed towards fetal-like progenitors in mice,” says lead author of the study, Sakurako Kobayashi. “However, the detailed mechanism by which this occurs, and whether this process also occurs in humans, remained unclear.”

 

To explore these questions, the researchers created collagen spheres, which are tiny balls of epithelial cells grown in purified collagen, from mouse and human intestinal cells. They then assessed gene expression in these spheres to clarify the mechanisms of inflammation-associated reprogramming.

 

“The results showed that culturing in collagen induced the expression of inflammation-associated and fetal-like genes in both human and mouse intestinal cells,” explains Shiro Yui, senior author. “As previously reported, the YAP/TAZ-TEAD axis definitely plays a central role in the induction of this distinctive gene expression signature, but this time we identified the cooperative transcriptional activity of Fra1 and RUNX2 in the process, which hammers the gene network centered on Fibronectin.”

 

Importantly, the representative genes that were activated in the human collagen spheres were also highly expressed in tissue samples taken from inflamed regions of the gut in patients with ulcerative colitis.

 

“Taken together, our findings demonstrate that collagen has a significant influence on inflammation and cellular reprogramming in both mice and humans,” says Kobayashi.

 

Given that some of the genes that were upregulated in the collagen spheres are also overexpressed in conditions such as colorectal cancer, it is possible that there is a link between the regenerative cascade and colorectal carcinogenesis. Thus, investigating the mechanisms of cell fate conversion using this model may enhance our understanding not only of how inflammation is influenced by the extracellular environment, but also how other disease processes occur in the gut.

 

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The article, “Collagen type I‑mediated mechanotransduction controls epithelial cell fate conversion during intestinal inflammation,” was published in Inflammation and Regeneration at DOI: 10.1186/s41232-022-00237-3

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JOURNAL

Inflammation and Regeneration

DOI

10.1186/s41232-022-00237-3 

ARTICLE TITLE

Collagen type I-mediated mechanotransduction controls epithelial cell fate conversion during intestinal inflammation

Study sheds novel insights on the

mechanism of melanin formation

Researchers report that a key transcription factor “Nrf3” regulates the process of melanin production in mouse and human cells

Peer-Reviewed Publication

DOSHISHA UNIVERSITY

 

IMAGE: RESEARCHERS FROM DOSHISHA UNIVERSITY SUGGEST THAT A TRANSCRIPTION FACTOR “NRF3” COORDINATES THE MELANOGENESIS PATHWAY IN RESPONSE TO FORSKOLIN OR ΑMSH VIA MACROPINOCYTOSIS AND AUTOPHAGY. THEY ALSO INDICATE THAT NELFINAVIR INHIBITED NRF3-MEDIATED MELANOGENESIS. view more 

CREDIT: IMAGE COURTESY: TSUYOSHI WAKU FROM DOSHISHA UNIVERSITY

The skin is presumably the largest and one of the most versatile body organs. By providing a physical barrier, it protects our body from environmental assaults. Melanin—a natural pigment produced by specialized skin cells called “melanocytes”—shields our body from the detrimental effects of ultraviolet (UV) radiation. UV radiation is responsible for DNA damage, genetic mutations, and can also lead to the onset of skin cancer. NF-E2-related factor 3 or “Nrf3,” a known transcription factor, or protein involved in the process of converting DNA into RNA, is abundantly found in the basal layer of the epidermis. However, its precise role in melanin production remains largely elusive.

Dr. Tsuyoshi Waku and his colleagues from the Laboratory for Genetic Code, the Faculty of Life and Medical Sciences and Graduate School of Life and Medical Sciences, Doshisha University, Japan have recently been able to discover the Nrf3-mediated mechanism of melanogenesis. Using in vitro experimentation, the research team showed that Nrf3 coordinates melanin production by regulating two key processes: macropinocytosis—engulfment and uptake of large amounts of fluids and membranes—and autophagy—recycling of old, damaged, abnormal cell components through controlled cellular breakdown. To this end, the researchers generated mouse malignant melanocyte (melanoma) B16F10 cells overexpressing Nrf3 or depleted the gene in normal human melanocyte (NHEM) cells and conducted a series of well-controlled experiments. This study was made available online on December 30, 2022 and published in volume 32 issue 1 of the journal Cell Reports on January 31, 2023.

Lead author of the study, Dr. Waku, Associate Professor at Doshisha University, muses, “This melanogenic study was started serendipitously. To investigate the effect of Nrf3 on the survival and growth of melanoma cells. We generated melanoma cells stably expressing Nrf3, and found by chance the positive effect of Nrf3 on melanogenesis.”

Co-authors, Sota Nakata, Haruka Masuda and Haruna Sumi, students of Doshisha University, discovered that Nrf3 upregulates the gene expression of core melanogenic factors, including Mitf, Tyr, Tyrp1, Pmel, and Oca2, in response to exogenous and endogenous inducers of melanin production, forskolin (Fsk), and αMSH. Moreover, they revealed that Nrf3 also induces the gene expression of Cln3, an autophagosome-related factor, for macropinocytic uptake of melanin precursors. In addition, they identified two autophagy-related genes targeted by Nrf3, i.e., Ulk2 and Gabarapl2, which contribute to the uptake of melanin precursors and the formation of melanosomes—specialized organelles responsible for the synthesis, storage, and transport of melanin.

Says co-author, Ayaka Wada, a student of Doshisha University, “We showed that Fsk or αMSH induced melanin production in B16F10 or NHEM cells in an Nrf3-dependent manner. Our immunoblotting and immunostaining results suggest that in response to Fsk, Nrf3 translocates from the ER membrane into the nucleus, where it induces melanin production and melanosome formation.” Iori Aketa, and Shuuhei Hirose, also students of the university and co-authors of the study, agree.

In fact, the researchers also found that Nrf3 triggers the recycling of skin tissues by facilitating the autolysosomal degradation of melanosomes. Furthermore, the team showed that αMSH—a hormone that stimulates melanocytes—causes Nrf3 activation and the subsequent formation of melanin, whereas nelfinavir, an HIV-1 protease inhibitor, inhibits Nrf3-mediated melanin formation.

Dr. Waku enthusiastically adds, “These findings demonstrated the physiological role of Nrf3 in the melanogenesis cascade, via the regulation of cellular membrane dynamics and the core melanogenic gene circuit, as well as the therapeutic potential of nelfinavir in skin hyperpigmentation conditions.”

The researchers are hopeful that their novel findings will be of interest not only to other scientists but also to cosmetic and pharmaceutical companies engaged in pigmentation research.

Professor Akira Kobayashi, the principal investigator of the Laboratory for Genetic Code at Doshisha University, concludes, “Our fundamental research purpose is to clarify the tumorigenic effect of Nrf3. This study implies the possibility of the pathophysiological correlation between Nrf3-mediated melanin production and melanoma malignancy.”

Melanin functions as a natural sunscreen. However, its excessive production causes melsasma, age spots, and freckles. Although further studies seem warranted, the study does seem to establish a likely association between melanin overproduction and skin cancer.

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About Dr. Tsuyoshi Waku from Doshisha University, Japan
Dr. Tsuyoshi Waku is serving as an Associate Professor at the Faculty of Life and Medical Sciences and Graduate School of Life and Medical Sciences, Doshisha University, Japan. He obtained his Ph.D. from Osaka University, Japan. Dr. Waku’s research group primarily conducts research in the field of gene expression, cancer development, transcription, translation, protein degradation, fat metabolism, cancer microenvironment, and tumor immunity. Dr. Waku has more than 35 publications to his credit. His work has been published in reputable journals such as Cell Reports, iScience, and Molecular and Cellular Biology.

Funding information
This study was supported in part by a grant-in-aid for Scientific Research (C) (19K07650 and  22K07219  to Tsuyoshi Waku); a grant in-aid from the Inamori Foundation (to Tsuyoshi Waku); a grant-in-aid from the Foundation for Promotion of Material Science and Technology of Japan (to Tsuyoshi Waku); grant-in-aid for Scientific Research (B) (20H03549 to Tsuyoshi Waku, 20H04135 to Akira Kobayashi); grant-in-aid for Challenging Research (Exploratory) (21K19743 to Akira Kobayashi); and grant-in-aid from the Mitsubishi Foundation (to Akira Kobayashi); grant-in-aid for JSPS Fellows (20J20194 to Shuuhei Hirose)

Media contact:
Organization for Research Initiatives & Development 
Doshisha University 
Kyotanabe, Kyoto 610-0394, JAPAN
E-mail：jt-ura@mail.doshisha.ac.jp
 

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JOURNAL

Cell Reports

DOI

10.1016/j.celrep.2022.111906 

METHOD OF RESEARCH

Experimental study

SUBJECT OF RESEARCH

Animals

ARTICLE TITLE

The CNC-family transcription factor Nrf3 coordinates the melanogenesis cascade through macropinocytosis and autophagy regulation

ARTICLE PUBLICATION DATE

31-Jan-2023

COI STATEMENT

The authors declare no competing interests.

Good news for athletes who are slow to recover from concussion

Most need just one more month to return to play

Peer-Reviewed Publication

AMERICAN ACADEMY OF NEUROLOGY

MINNEAPOLIS - A new study suggests that athletes who recover more slowly from concussion may be able to return to play with an additional month of recovery beyond the typical recovery time, according to a new study published in the January 18, 2023, online issue of Neurology®, the medical journal of the American Academy of Neurology. Slow recovery was defined as taking more than 14 days for symptoms to resolve or taking more than 24 days to return to play, both of which are considered the typical recovery times for about 80% of athletes with concussion.

“Although an athlete may experience a slow or delayed recovery, there is reason to believe recovery is achievable with additional time and injury management,” said study author Thomas W. McAllister, MD, of the Indiana University School of Medicine in Indianapolis. “This is an encouraging message that may help to relieve some of the discouragement that athletes can feel when trying to return to their sport. While some athletes took longer than 24 days to return to play, we found that three-quarters of them were able to return to sports if given just one more month to recover.”

The study looked at 1,751 college athletes who had been diagnosed with a concussion by a team physician. Of the athletes, 63% were male and 37% were female. Male athletes participated primarily in football, soccer and basketball. Female athletes participated primarily in soccer, volleyball and basketball.

Participants were evaluated five times: within six hours after their injury, one to two days later, once free of symptoms, once cleared to return to play and at six months.

Participants reported symptoms daily to medical staff, up to 14 days following injury and then weekly if they had not yet returned to play.

A total of 399 athletes, or 23%, had a slow recovery.

Researchers found that of the athletes who took longer than 24 days to return to play, more than three-fourths, or 78%, were able to return to play within 60 days of injury, and four-fifths, or 83%, were able to return to play within 90 days of injury. Only 11% had not returned to play six months after injury.

For the slow recovery group, the average time for returning to play was 35 days after injury, compared to 13 days in the overall group.

“The results of this study provide helpful information for athletes and medical teams to consider in evaluating expectations and making difficult decisions about medical disqualification and the value of continuing in their sport,” McAllister said.

A limitation of the study is that participants were all collegiate varsity athletes and may not be representative of other age groups or levels of sport, and the results may not apply to other types of mild brain injuries.

The study was supported by the Grand Alliance Concussion Assessment, Research, and Education Consortium, National Collegiate Athletic Association, and the Department of Defense.

Learn more about concussion at BrainandLife.org, home of the American Academy of Neurology’s free patient and caregiver magazine focused on the intersection of neurologic disease and brain health. Follow Brain & Life® on Facebook, Twitter and Instagram.

When posting to social media channels about this research, we encourage you to use the hashtags #Neurology and #AANscience.

The American Academy of Neurology is the world’s largest association of neurologists and neuroscience professionals, with over 38,000 members. The AAN is dedicated to promoting the highest quality patient-centered neurologic care. A neurologist is a doctor with specialized training in diagnosing, treating and managing disorders of the brain and nervous system such as Alzheimer’s disease, stroke, migraine, multiple sclerosis, concussion, Parkinson’s disease and epilepsy.

For more information about the American Academy of Neurology, visit AAN.com or find us on Facebook, Twitter, Instagram, LinkedIn and YouTube.

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JOURNAL

Neurology

‘Ghostly’ neutrinos provide new path to study protons

Scientists have discovered a new way to investigate the structure of protons using neutrinos, known as ‘ghost particles.’

Peer-Reviewed Publication

UNIVERSITY OF ROCHESTER

 

IMAGE: MEMBERS OF THE INTERNATIONAL COLLABORATION MINERVA, INCLUDING UNIVERSITY OF ROCHESTER RESEARCHERS, USED A PARTICLE ACCELERATOR AT FERMILAB—A PORTION OF WHICH IS SHOWN IN A STYLIZED IMAGE ABOVE—TO CREATE A BEAM OF NEUTRINOS TO INVESTIGATE THE STRUCTURE OF PROTONS. THE WORK WAS PART OF THE MINERVA EXPERIMENT, A PARTICLE PHYSICS EXPERIMENT TO STUDY NEUTRINOS. view more 

CREDIT: REIDAR HAHN/FERMILAB

Neutrinos are one of the most abundant particles in our universe, but they are notoriously difficult to detect and study: they don’t have an electrical charge and have nearly no mass. They are often referred to as “ghost particles” because they rarely interact with atoms.

But because they are so abundant, they play a large role in helping scientists answer fundamental questions about the universe.

In groundbreaking research described in Nature—led by researchers from the University of Rochester—scientists from the international collaboration MINERvA have, for the first time, used a beam of neutrinos at the Fermi National Accelerator Laboratory, or Fermilab, to investigate the structure of protons.

MINERvA is an experiment to study neutrinos, and the researchers did not set out to study protons. But their feat, once thought impossible, offers scientists a new way of looking at the small components of an atom’s nucleus.

“While we were studying neutrinos as part of the MINERvA experiment, I realized a technique I was using might be applied to investigate protons,” says Tejin Cai, the paper’s first author. Cai, who is now a postdoctoral research associate at York University, conducted the research as a PhD student of Kevin McFarland, the Dr. Steven Chu Professor in Physics at Rochester and key member of the University’s Neutrino Group. “We weren’t sure at first if it would work, but we ultimately discovered we could use neutrinos to measure the size and shape of the protons that make up the nuclei of atoms. It’s like using a ghost ruler to make a measurement.”

Using particle beams to measure protons 

Atoms, and the protons and neutrons that make up an atom’s nucleus, are so small that researchers have a difficult time measuring them directly. Instead, they build a picture of the shape and structure of an atom’s components by bombarding atoms with a beam of high-energy particles. They then measure how far and at what angles the particles bounce off the atom’s components.

Imagine, for example, throwing marbles at a box. The marbles would bounce off the box at certain angles, enabling you to determine where the box was—and to determine its size and shape—even if the box was not visible to you.

“This is a very indirect way of measuring something, but it allows us to relate the structure of an object—in this case, a proton—to how many deflections we see in different angles,” McFarland says.

What can neutrino beams tell us? 

Researchers first measured the size of protons in the 1950s, using an accelerator with beams of electrons at Stanford University’s linear accelerator facility. But instead of using beams of accelerated electrons, the new technique developed by Cai, McFarland, and their colleagues, uses beams of neutrinos.

While the new technique does not produce a sharper image than the old technique, McFarland says, it may give scientists new information about how neutrinos and protons interact—information they can currently only infer using theoretical calculations or a combination of theory and other measurements.

In comparing the new technique with the old, McFarland likens the process to seeing a flower in normal, visible light and then looking at the flower under ultraviolet light.

“You are looking at the same flower, but you can see different structures under the different kinds of light,” McFarland says. “Our image isn’t more precise, but the neutrino measurement provides us with a different view.”

Specifically, they are hoping to use the technique to separate the effects related to neutrino scattering on protons from the effects related to neutrino scattering on atomic nuclei, which are bound collections of protons and neutrons.

“Our previous methods for predicting neutrino scattering from protons all used theoretical calculations, but this result directly measures that scattering,” Cai says.

McFarland adds, “By using our new measurement to improve our understanding of these nuclear effects, we will better be able to carry out future measurements of neutrino properties.”

The technical challenge of experimenting with neutrinos

Neutrinos are created when atomic nuclei either come together or break apart. The sun is a large source of neutrinos, which are a byproduct of the sun’s nuclear fusion. If you stand in the sunlight, for example, trillions of neutrinos will harmlessly pass through your body every second.

Even though neutrinos are more abundant in the universe than electrons, it is harder for scientists to experimentally harness them in large numbers: neutrinos pass through matter like ghosts, while electrons interact with matter far more frequently.

“Over the course of a year, on average, there would only be interactions between one or two neutrinos out of the trillions that go through your body every second,” Cai says. “There’s a huge technical challenge in our experiments in that we have to get enough protons to look at, and we have to figure out how to get enough neutrinos through that big assembly of protons.”

Using a neutrino detector

The researchers solved this problem in part by using a neutrino detector containing a target of both hydrogen and carbon atoms. Typically researchers use only hydrogen atoms in experiments to measure protons. Not only is hydrogen the most abundant element in the universe, it’s also the simplest, as a hydrogen atom contains only a single proton and electron. But a target of pure hydrogen wouldn’t be sufficiently dense for enough neutrinos to interact with the atoms.

“We’re performing a ‘chemical trick’, so to speak, by binding the hydrogen up into hydrocarbon molecules that make it able to detect sub-atomic particles,” McFarland says.

The MINERvA group conducted their experiments using a high-power, high-energy particle accelerator, located at Fermilab. The accelerator produces the strongest source of high-energy neutrinos on the planet.

The researchers struck their detector made of hydrogen and carbon atoms with the beam of neutrinos and recorded data for nearly nine years of operation.

To isolate only the information from the hydrogen atoms, the researchers then had to subtract the background “noise” from the carbon atoms.

“The hydrogen and carbon are chemically bonded together, so the detector sees interactions on both at once,” Cai says. “I realized that a technique I was using to study interactions on carbon could also be used to see hydrogen all by itself once you subtract the carbon interactions. A big part of our job was subtracting the very large background from neutrinos scattering on the protons in the carbon nucleus.”

Says Deborah Harris, a professor at York University and a co-spokesperson for MINERvA, “When we proposed MINERvA, we never thought we’d be able to extract measurements from the hydrogen in the detector. Making this work required great performance from the detector, creative analysis from scientists, and years of running” the accelerator at Fermilab.

The impossible becomes possible

McFarland, too, initially thought it would be close to impossible to use neutrinos to precisely measure the signal from the protons.

“When Tejin and our colleague Arie Bodek (the George E. Pake Professor of Physics at Rochester) first suggested trying this analysis, I thought it would be too difficult,” McFarland says. “But the old view of protons has been very thoroughly explored, so we decided to try this technique to get a new view—and it worked.”

The collective expertise of MINERvA’s scientists and the collaboration within the group was essential in accomplishing the research, Cai says.

“The result of the analysis and the new techniques developed highlight the importance of being creative and collaborative in understanding data,” he says. “While a lot of the components for the analysis already existed, putting them together in the right way really made a difference, and this cannot be done without experts with different technical backgrounds sharing their knowledge to make the experiment a success.”

In addition to providing more information about the common matter that comprises the universe, the research is important for predicting neutrino interactions for other experiments that are trying to measure the properties of neutrinos. These experiments include the Deep Underground Neutrino Experiment (DUNE), the Imaging Cosmic And Rare Underground Signals (ICARUS) neutrino detector, and T2K neutrino experiments in which McFarland and his group are involved.

“We need detailed information about protons to answer questions like which neutrinos have more mass than others and whether or not there are differences between neutrinos and their anti-matter partners,” Cai says. “Our work is one step forward in answering the fundamental questions about neutrino physics that are the goal of these big science projects in the near future.”

 

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JOURNAL

Nature

DOI

10.1038/s41586-022-05478-3 

ARTICLE TITLE

Measurement of the axial vector form factor from antineutrino–proton scattering

ARTICLE PUBLICATION DATE

1-Feb-2023

New research computes first step toward predicting lifespan of electric space propulsion systems

Peer-Reviewed Publication

UNIVERSITY OF ILLINOIS GRAINGER COLLEGE OF ENGINEERING

 

IMAGE: ILLUSTRATION OF THE HALL THRUSTER PLUMES IMPACTING THE CARBON SURFACES AT THE ATOMISTIC LEVEL. view more 

CREDIT: THE GRAINGER COLLEGE OF ENGINEERING AT THE UNIVERSITY OF ILLINOIS URBANA-CHAMPAIGN

Electric space propulsion systems use energized atoms to generate thrust. The high-speed beams of ions bump against the graphite surfaces of the thruster, eroding them a little more with each hit, and are the systems' primary lifetime-limiting factor. When ion thrusters are ground tested in an enclosed chamber, the ricocheting particles of carbon from the graphite chamber walls can also redeposit back onto the thruster surfaces. This changes the measured performance characteristics of the thruster.

Researchers at the University of Illinois Urbana-Champaign used data from low-pressure chamber experiments and large-scale computations to develop a model to better understand the effects of ion erosion on carbon surfaces —the first step in predicting its failure.

“We need an accurate assessment of the ion erosion rate on graphite to predict thruster life, but testing facilities have reported varying sputtering rates, leading to large uncertainties in predictions,” said Huy Tran, a Ph.D. student in the Department of Aerospace Engineering at UIUC.

Tran said it is difficult to replicate the environment of space in a laboratory chamber because it is difficult to construct a sufficiently large chamber to avoid ion-surface interactions at the chamber walls. And although graphite is typically used for the accelerator grid and pole covers in the thruster, there isn’t agreement on which type of graphite is most resistant to erosion, known as sputtering.

“The fundamental problem with testing an ion thruster in a chamber is that the thruster is continuously spitting out xenon ions that also impact with the chamber walls made out of graphite panels, but there are no chamber walls in space,” Tran said. “When these xenon ions hit the graphite panels, they also sputter out carbon atoms that redeposit on the accelerator grids. So instead of the grid becoming thinner and thinner because of thruster erosion, some people have seen in experiments that the grids get thicker with time because the carbon is coming back from the chamber walls.”

The simulation resolved the limitations and uncertainties in the experimental data and the researchers gained insight into a critical phenomenon.

“Whether it is pyrolytic graphite on the grided ion optics, isotropic graphite on the pole covers, or poco graphite or anisotropic graphite on the chamber walls, our molecular dynamics simulations show that the sputtering rates and mechanisms are identical across all these different referenced structures,” said Huck Beng Chew, Tran’s adviser.

He said the sputtering process creates a unique carbon structure during the bombardment process. Watch a video of the simulation showing a close-up view of the xenon ion traveling at hypersonic velocity, impacting the carbon structure.

“When the ions come and damage the surface, they transform the surface into an amorphous-like structure regardless of the initial carbon structure,” Chew said. “You end up with a sputtered surface with the same unique structural characteristics. This is one of the main findings that we have observed from our simulations.”

Chew said they even tried it with diamond. Regardless of the much lower initial porosity and the more rigid bond configuration, they got the same sputtered structure.

“The model we developed bridges the molecular dynamics simulation results to the experimental data,” Chew said. “The next thing we want to look at is the evolving surface morphology over time as you put more and more xenon ions into the system. This is relevant to ion thrusters for deep space exploration.”

The research is part of a NASA center known as the Joint Advanced Propulsion Institute which includes researchers at nine universities, including UIUC aerospace engineering faculties Chew, Debbie Levin, and Joshua Rovey who leads the Illinois team.

The simulations were performed using NCSA’s Delta, a supercomputing facility at Illinois.

The paper, “Surface morphology and carbon structure effects on sputtering: Bridging scales between molecular dynamics simulations and experiments,” is written by Huy Tran and Huck Beng Chew. It is published in the journal Carbon.

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JOURNAL

Carbon

DOI

10.1016/j.carbon.2023.01.015 

ARTICLE TITLE

Surface morphology and carbon structure effects on sputtering: Bridging scales between molecular dynamics simulations and experiments

Dogs’ average age at cancer diagnosis is associated with size, sex, breed

Giant breeds, males and purebred dogs tend to receive a cancer diagnosis at a relatively younger age, informing potential screening guidelines

Peer-Reviewed Publication

PLOS

 

IMAGE: THE STUDY, INVOLVING OVER 3,000 CANCER-DIAGNOSED DOGS, FOUND THAT ALL DOGS SHOULD BEGIN CANCER SCREENING AT AGE 7, BUT CERTAIN BREEDS MAY BENEFIT FROM SCREENING STARTING AS EARLY AS AGE 4. view more 

CREDIT: PETDX, CC-BY 4.0 (HTTPS://CREATIVECOMMONS.ORG/LICENSES/BY/4.0/)

A new analysis has determined median ages of cancer diagnosis for dogs with different characteristics, providing support for the establishment of cancer screening guidelines that vary according to breed or weight. Jill Rafalko of PetDx in La Jolla, California, and colleagues present these findings in the open-access journal PLOS ONE on February 1, 2023.

More adult dogs die from cancer than from any other cause. Just as in humans, detecting canine cancer earlier can enable more effective treatment. New, noninvasive blood tests for dogs can detect tumor DNA long before other signs of cancer arise. However, formal guidelines for when dogs should be screened using these tests are lacking.

To aid establishment of such guidelines, Rafalko and colleagues sought to determine the median age at cancer diagnosis of dogs with different characteristics. Their analysis included 3,452 dogs with cancer in the U.S.

They found that the median age at cancer diagnosis for dogs weighing 75 kilograms or more was 5 years, compared to 11 years for dogs weighing 2.5 to 5 kilograms. The mean diagnosis age for purebred dogs was 8.2 years, compared to 9.2 years for dogs whose breed was described as mixed or “other.”

Among breeds with enough representation in the study, the researchers were able to determine that Mastiffs, Saint Bernards, Great Danes, and Bulldogs had the youngest median diagnosis age, at approximately 6 years. Irish Wolfhounds, Vizslas, and Bernese Mountain Dogs had median diagnosis ages of 6.1 to 7 years. At 11.5 years, the Bichon Frise had the oldest median diagnosis age.

Female dogs were typically diagnosed at older ages than males, and dogs that were neutered were diagnosed later than intact dogs.

The researchers also developed a statistical model to predict median diagnosis age based on weight, which could be applied to breeds with less representation in the study and to mixed-breed dogs.

Considering these findings in combination with evidence from prior studies, the researchers propose that canine cancer detection could be improved through blood test-based screening beginning 2 years before a dog reaches the median diagnosis age for their breed or weight.

The authors add: “Dogs now have a new option for cancer screening called ‘liquid biopsy’ which, similar to the human version of this test, leverages next-generation sequencing technology to detect multiple types of cancer using a simple blood draw. However, the age to start screening for cancer in dogs can vary depending on their breed or weight. Our study, involving over 3,000 cancer-diagnosed dogs, found that all dogs should begin cancer screening at age 7, but certain breeds may benefit from screening starting as early as age 4.”

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In your coverage please use this URL to provide access to the freely available article in PLOS ONE: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0280795

Citation: Rafalko JM, Kruglyak KM, McCleary-Wheeler AL, Goyal V, Phelps-Dunn A, Wong LK, et al. (2023) Age at cancer diagnosis by breed, weight, sex, and cancer type in a cohort of more than 3,000 dogs: Determining the optimal age to initiate cancer screening in canine patients. PLoS ONE 18(2): e0280795. https://doi.org/10.1371/journal.pone.0280795

Author Countries: USA

Funding: This study received funding from PetDx. The funder had the following involvement with the study: study design, data collection and analysis, decision to publish, and preparation of the manuscript.

The risk of cancer and cancer-associated mortality in dogs is known to vary greatly depending on breed. 

In this article, researchers studied the median age at which a number of dog breeds are diagnosed with cancer. Of the 43 breeds represented, Mastiffs had the youngest median age at cancer diagnosis (5 years), while Bichon Frises had the oldest median age (11.5 years). The median age of cancer diagnosis was also seen to be lower for purebred dogs than for mixed breed dogs. The median age found for each breed may assist in establishing the age at which cancer screening should be initiated for individual dogs, to increase likelihood of early detection and treatment. Note: For display purposes, outliers are not presented for bars comparing purebred and mixed breed dogs.

CREDIT

Anne-Lise Paris (www.in-graphidi.com), PLOS, CC-BY 4.0 (https://creativecommons.org/licenses/by/4.0/)

JOURNAL

PLoS ONE

DOI

10.1371/journal.pone.0280795 

METHOD OF RESEARCH

Observational study

SUBJECT OF RESEARCH

Animals

ARTICLE TITLE

Age at cancer diagnosis by breed, weight, sex, and cancer type in a cohort of more than 3,000 dogs: Determining the optimal age to initiate cancer screening in canine patients

ARTICLE PUBLICATION DATE

1-Feb-2023

COI STATEMENT

All authors are employed by and hold vested or unvested equity in PetDx. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

LJI scientists uncover the structure and function of Inmazeb, the first FDA-approved drug for Ebola virus infection

New findings emphasize the benefits of antibody cocktails over monotherapy approaches

Peer-Reviewed Publication

LA JOLLA INSTITUTE FOR IMMUNOLOGY

 

IMAGE: THE NEW STUDY SHOWS HOW THREE ANTIBODIES (LIGHT BLUE, DARK BLUE, AND YELLOW) USED IN INMAZEB (REGN-EB3) BIND TO DIFFERENT REGIONS OF THE EBOLA VIRUS GLYCOPROTEIN (GREY) TO COMBAT INFECTION. IMAGE CREDIT: ETHAN MACKENZIE (PHOSPHO BIOMEDICAL ANIMATION) view more 

CREDIT: ETHAN MACKENZIE (PHOSPHO BIOMEDICAL ANIMATION)

LA JOLLA, CA—Scientists at La Jolla Institute for Immunology (LJI) have uncovered the structure and function of the first FDA-approved treatment for Zaire ebolavirus (Ebola virus). 

Inmazeb (REGN-EB3), developed by Regeneron, is a three-antibody cocktail designed to target the Ebola virus glycoprotein. The drug was first approved for clinical use in October 2020, but its exact mechanism of action has remained unclear.

In the cover story of the latest issue of Cell Host & Microbe, LJI researchers present a high-resolution, 3D structure of the three antibodies as they bind to the Ebola virus glycoprotein (the viral protein that launches Ebola virus infection). The model reveals new information about both the drug and the virus, and how their interaction fights infection and protects against future viral mutations. 

“Before this, we had a general idea of what the drug was doing, but we didn’t know exactly how,” says LJI President and CEO Erica Ollmann Saphire, Ph.D., who served as senior author of the study. “We now know which specific amino acids the antibodies are latching onto and how their binding affects the viral glycoprotein.”

The new research also shows the potential for Inmazeb in treating additional species of Ebolavirus. 

How the antibody cocktail works

At 3.1 angstroms, the 3D structure is the highest-resolution image of the Ebola virus surface protein ever assembled using asymmetric reconstruction. The researchers achieved this detailed view through an imaging technique called cryogenic electron microscopy (cryo-EM).

“It’s like getting mugshots of a protein,” said first author Vamseedhar Rayaprolu, Ph.D., who spearheaded the project as a postdoctoral associate at LJI and now serves at The Pacific Northwest Center for Cryo-EM. “We take photos of the complex that is frozen in all different angles and then stitch them together to get a 3D model.”

Thanks to these images, the LJI team immediately made a discovery not just about the drug, but also about Ebola virus itself. While the overall structure of the Ebola glycoprotein has been known for some time, one region had yet to be modeled effectively—the β17-β18 loop on the protein’s glycan cap.

“This piece is normally too floppy to be imaged,” said Rayaprolu, “but when the antibodies were bound to the virus, they locked the loop into place and we were able to finally capture its location and structure.”

The team then confirmed that the drug’s three antibodies bind the glycoprotein at distinct, non-overlapping locations, maximizing their effectiveness by minimizing their redundancy. 

Atoltivimab (REGN3470) is the specific antibody that binds the β17-β18 loop. When bound, this antibody can serve as a signal to attract the immune system, flagging infected cells to be killed via effector functions. 

A second antibody, called odesivimab (REGN3471), binds to amino acids on the glycoprotein’s receptor-binding site, preventing the virus from attaching itself to human cells. 

The third antibody, called maftivimab (REGN3479), binds and warps the glycoprotein’s internal fusion loop, which the virus requires to drive itself into a cell. The researchers also found evidence that maftivimab may be valuable in future therapies against other types of Ebolaviruses.

Fighting more than one virus

"Like with SARS-CoV-2, Ebola virus has changed over time and become different than the original virus," says study collaborator Robert Davey, Ph.D., Professor in the National Emerging Infectious Diseases Laboratories (NEIDL), of the Boston University Chobanian & Avedisian School of Medicine. As Davey points out, Ebola viruses aren't the only dangerous members of the larger Filovirus family. This family includes closely related Ebolavirus species, such as Sudan ebolavirus (a 2022 outbreak of Sudan ebolavirus killed at least 55 people in Uganda) and the more distantly related Marburg virus.

Through a series of escape studies led by study collaborators in Davey's lab and at Regeneron, the team found that Inmazeb could potentially protect against several viruses in the Ebolavirus genus of Filoviruses, including Sudan ebolavirus. 

The key appears to be the maftivimab antibody. Maftivimab's target, the viral glycoprotein's internal fusion loop, is conserved across these Ebolaviruses. This means the loop structure has not changed significantly, even as other parts of the virus have mutated over time.

"We found that, in general, the antibodies in Inmazeb could be effective against the more closely related viruses," says Davey. "But for the more distantly related species, such as Marburg, more work needs to be done to devise a new antibody cocktail."

Could Inmazeb also combat new Ebola virus variants? The researchers found that—in the presence of all three antibodies—Ebola virus has to undergo ten rounds of replication and multiple mutations to partially escape the effects of the drug. In contrast, using any single antibody alone leads to escape mutations within only one or two passages. 

This finding suggests that Inmazeb can provide lasting immunity against variants. The new findings may also guide the development of novel antibody drugs that target the glycoprotein more broadly or effectively. 

“We now understand how subtle shifts in the landing site of different antibodies impact function,” says Rayaprolu. “This tells us the differences between more or less effective immune responses.”

“Knowing exactly where a drug contacts the virus helps us predict whether it is likely to still work on a new viral variant,” adds Saphire. “These methods and the insights from our research collaborators will be integral to the development of next-generation vaccines."

Additional authors of the study, “Structure of the Inmazeb cocktail and resistance to Ebola virus escape,” include Benjamin O. Fulton, Ashique Rafique, Emilia Arturo, Dewight Williams, Chitra Hariharan, Heather Callaway, Amar Parvate, Sharon L. Schendel, Diptiben Parekh, Sean Hui, Kelly Shaffer, Kristen E. Pascal, Elzbieta Wloga, Stephanie Giordano, Nicole Negron, Min Ni, Richard Copin, Gurinder S. Atwal, Matthew Franklin, Ruth Mabel Boytz, Callie Donahue, Alina Baum, and Christos A. Kyratsous, researchers at Regeneron, Boston University and La Jolla Institute for Immunology.

The study was supported by the NIH National Institute of Allergy and Infectious Diseases (grant U19 AI142790), the Consortium for Immunotherapeutics against Emerging Viral Threats, and the U.S. Department of Health and Health Services Contract No. HHSO100201700016C (Regeneron). Additional funding was provided by the Department of Health and Human Services, the NIH National Cancer Institute (grant ACB-12002), and the NIH National Institute of General Medical Sciences (grants AGM-12006 and P30GM138396). 

DOI: 10.1016/j.chom.2023.01.002

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About La Jolla Institute

The La Jolla Institute for Immunology is dedicated to understanding the intricacies and power of the immune system so that we may apply that knowledge to promote human health and prevent a wide range of diseases. Since its founding in 1988 as an independent, nonprofit research organization, the Institute has made numerous advances leading toward its goal: life without disease. Visit lji.org for more information.

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JOURNAL

Cell Host & Microbe

DOI

10.1016/j.chom.2023.01.002 

METHOD OF RESEARCH

Experimental study

SUBJECT OF RESEARCH

Cells

ARTICLE TITLE

Structure of the Inmazeb cocktail and resistance to Ebola virus escape

ARTICLE PUBLICATION DATE

27-Jan-2023

COI STATEMENT

The Regeneron employees have stock and/or options in the company. C.A.K. is an officer of the company. The antibodies are patented: WO/2016/123019.