Biology

Researchers Shed Light On The Mechanism Of Magnetic Sensing in Birds (Biology)

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Humans perceive the world around them with five senses – vision, hearing, taste, smell and touch. Many other animals are also able to sense the Earth’s magnetic field. For some time, a collaboration of biologists, chemists and physicists centred at the Universities of Oldenburg (Germany) and Oxford (UK) have been gathering evidence suggesting that the magnetic sense of migratory birds such as European robins is based on a specific light-sensitive protein in the eye. In the current edition of the journal Nature, this team demonstrate that the protein cryptochrome 4, found in birds’ retinas, is sensitive to magnetic fields and could well be the long-sought magnetic sensor.

First author Jingjing Xu, a doctoral student in Henrik Mouritsen’s research group in Oldenburg, took a decisive step toward this success. After extracting the genetic code for the potentially magnetically sensitive cryptochrome 4 in night-migratory European robins, she was able, for the first time, to produce this photoactive molecule in large quantities using bacterial cell cultures. Christiane Timmel’s and Stuart Mackenzie’s groups in Oxford then used a wide range of magnetic resonance and novel optical spectroscopy techniques to study the protein and demonstrate its pronounced sensitivity to magnetic fields.

The team also deciphered the mechanism by which this sensitivity arises – another important advance. “Electrons that can move within the molecule after blue-light activation play a crucial role”, explains Mouritsen. Proteins like cryptochrome consist of chains of amino acids: robin cryptochrome 4 has 527 of them. Oxford’s Peter Hore and Oldenburg physicist Ilia Solov’yov performed quantum mechanical calculations supporting the idea that four of the 527 – known as tryptophans – are essential for the magnetic properties of the molecule. According to their calculations, electrons hop from one tryptophan to the next generating so-called radical pairs which are magnetically sensitive. To prove this experimentally, the team from Oldenburg produced slightly modified versions of the robin cryptochrome, in which each of the tryptophans in turn was replaced by a different amino acid to block the movement of electrons.

Using these modified proteins, the Oxford chemistry groups were able to demonstrate experimentally that electrons move within the cryptochrome as predicted in the calculations – and that the generated radical pairs are essential to explain the observed magnetic field effects.

The Oldenburg team also expressed cryptochrome 4 from chickens and pigeons. When studied in Oxford, the proteins of these species, which do not migrate, exhibit similar photochemistry to that of the migratory robin, but appear markedly less magnetically sensitive.

“We think these results are very important because they show for the first time that a molecule from the visual apparatus of a migratory bird is sensitive to magnetic fields” says Mouritsen. But, he adds, this is not definitive proof that cryptochrome 4 is the magnetic sensor the team is looking for. In all experiments, the researchers examined isolated proteins in the laboratory. The magnetic fields used were also stronger than the Earth’s magnetic field. “It therefore still needs to be shown that this is happening in the eyes of birds” Mouritsen stresses. Such studies are not yet technically possible.

However, the authors think the proteins involved could be significantly more sensitive in their native environment. In cells in the retina, the proteins are probably fixed and aligned, increasing their sensitivity to the direction of the magnetic field. Moreover, they are also likely to be associated with other proteins that could amplify the sensory signals. The team is currently searching for these as yet unknown interaction partners.

Hore says “if we can prove that cryptochrome 4 is the magnetic sensor we will have demonstrated a fundamentally quantum mechanism that makes animals sensitive to environmental stimuli a million times weaker than previously thought possible”.

The cooperation between Oldenburg and Oxford is funded by a 6-year Synergy Grant from the European Research Council (ERC) with the title ‘QuantumBirds’. The collaboration is also a key part of the Collaborative Research Center, ‘Magnetoreception and Navigation in Vertebrates’ (SFB 1372) funded by the German Research Foundation (DFG), and Ilia Solov’yov is a Lichtenberg Professor funded by the Volkswagen Stiftung.

Featured image: Migratory birds such as European robins can sense the Earth’s magnetic field. Now researchers show for the first time that a molecule from their visual apparatus is sensitive to magnetic field. © Corinna Langebrake and Ilia Solov’yov

Reference: Xu, J., Jarocha, L.E., Zollitsch, T. et al. Magnetic sensitivity of cryptochrome 4 from a migratory songbird. Nature 594, 535–540 (2021). https://doi.org/10.1038/s41586-021-03618-9

Provided by University of Oldenburg

Planetary Science

Life in These Star-systems Could Have Spotted Earth (Planetary Science)

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Scientists at Cornell University and the American Museum of Natural History have identified 2,034 nearby star-systems – within the small cosmic distance of 326 light-years – that could find Earth merely by watching our pale blue dot cross our sun.

That’s 1,715 star-systems that could have spotted Earth since human civilization blossomed about 5,000 years ago, and 319 more star-systems that will be added over the next 5,000 years.

Exoplanets around these nearby stars have a cosmic front-row seat to see if Earth holds life, the scientists said in research published June 23 in Nature.

“From the exoplanets’ point-of-view, we are the aliens,” said Lisa Kaltenegger, professor of astronomy and director of Cornell’s Carl Sagan Institute, in the College of Arts and Sciences.

“We wanted to know which stars have the right vantage point to see Earth, as it blocks the Sun’s light,” she said. “And because stars move in our dynamic cosmos, this vantage point is gained and lost.”

Kaltenegger and astrophysicist Jackie Faherty, a senior scientist at the American Museum of Natural History and co-author of “Past, Present and Future Stars That Can See Earth As A Transiting Exoplanet,” used positions and motions from the European Space Agency’s Gaia eDR3 catalog to determine which stars enter and exit the Earth Transit Zone – and for how long.

“Gaia has provided us with a precise map of the Milky Way galaxy,” Faherty said, “allowing us to look backward and forward in time, and to see where stars had been located and where they are going.”

Of the 2,034 star-systems passing through the Earth Transit Zone over the 10,000-year period examined, 117 objects lie within about 100 light-years of the sun and 75 of these objects have been in the Earth Transit Zone since commercial radio stations on Earth began broadcasting into space about a century ago.

“Our solar neighborhood is a dynamic place where stars enter and exit that perfect vantage point to see Earth transit the Sun at a rapid pace,” Faherty said.

Included in the catalog of 2,034 star-systems are seven known to host exoplanets. Each one of these worlds has had or will have an opportunity to detect Earth, just as Earth’s scientists have found thousands of worlds orbiting other stars through the transit technique.

By watching distant exoplanets transit – or cross – their own sun, Earth’s astronomers can interpret the atmospheres backlit by that sun. If exoplanets hold intelligent life, they can observe Earth backlit by the sun and see our atmosphere’s chemical signatures of life.

The Ross 128 system, with a red dwarf host star located in the Virgo constellation, is about 11 light-years away and is the second-closest system with an Earth-size exoplanet (about 1.8 times the size of our planet). Any inhabitants of this exoworld could have seen Earth transit our own sun for 2,158 years, starting about 3,057 years ago; they lost their vantage point about 900 years ago.

The Trappist-1 system, at 45 light-years from Earth, hosts seven transiting Earth-size planets – four of them in the temperate, habitable zone of that star. While we have discovered the exoplanets around Trappist-1, they won’t be able to spot us until their motion takes them into the Earth Transit Zone in 1,642 years. Potential Trappist-1 system observers will remain in the cosmic Earth transit stadium seats for 2,371 years.

“Our analysis shows that even the closest stars generally spend more than 1,000 years at a vantage point where they can see Earth transit,” Kaltenegger said. “If we assume the reverse to be true, that provides a healthy timeline for nominal civilizations to identify Earth as an interesting planet.”

The James Webb Space telescope – expected to launch later this year — is set to take a detailed look at several transiting worlds to characterize their atmospheres and ultimately search for signs of life.

The Breakthrough Starshot initiative is an ambitious project underway that is looking to launch a nano-sized spacecraft toward the closest exoplanet detected around Proxima Centauri – 4.2 light-years from us – and fully characterize that world.

“One might imagine that worlds beyond Earth that have already detected us, are making the same plans for our planet and solar system,” said Faherty. “This catalog is an intriguing thought experiment for which one of our neighbors might be able to find us.”

The Carl Sagan Institute, the Heising Simons Foundation and the Breakthrough Initiatives program supported this research.

Reference: Kaltenegger, L., Faherty, J.K. Past, present and future stars that can see Earth as a transiting exoplanet. Nature 594, 505–507 (2021). https://doi.org/10.1038/s41586-021-03596-y

Provided by Cornell University

Medicine

Platinum-chemotherapy Can Enhance the Treatment Resistance of Ovarian Cancer Cells (Medicine)

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Researchers from Karolinska Institutet have discovered how platinum-chemotherapy can enhance the treatment resistance of ovarian cancer cells, by progressively changing the cancer cell-intrinsic adhesion signaling and cell-surrounding microenvironment.

Platinum chemotherapy is standard treatment in ovarian cancers, but treatment resistance commonly develops. The extracellular matrix (ECM)-derived biochemical and mechanical cues in the tumor microenvironment are known to contribute to the ability of cancer cells to metastasize and resist treatment. However, how the dynamic communication between the cancer cells and the ECM is affected by, or influences the disease progression and chemotherapy, have remained elusive.

A new study led by Kaisa Lehti, researcher at the Department of Microbiology, Tumor and Cell Biology at KI, and published in Nature Communications, shows that the ECM microenvironment is modulated in metastasis and following chemotherapy. Changes in the ECM proteins variably altered the cell death response of the tumour cells.

“Particularly in the most aggressive solid tumor tissues, cancer cells are surrounded by a prominent fibrotic network of proteins like collagens, known as the extracellular matrix (ECM) and also defined as the matrisome when considered with various associated factors including cytokines and chemokines. The ECM/matrisome is produced largely by stromal cells, but sensed and remodeled collectively by the cancer cells and the cells of the fibrotic tumor stroma. In tumor cells, specific ECM signaling in stiff microenvironment critically increased their resistance against platinum-mediated, apoptosis-inducing DNA damage”, Kaisa Lehti explains.

Read the full article in Nature Communications

The study included key clinical collaboration with University of Turku and Turku University Hospital as well as Karolinska University Hospital and was completed in collaboration with Norwegian University of Science and Technology, NTNU. It was funded by the KI Strategic Research Program in Cancer (KI Cancer Research), the Swedish Cancer Society, the Swedish Research Council, Sigrid Juselius Foundation, the Finnish Cancer Foundation, Orion Research Foundation, K. Albin Johanssons Foundation, Emil Aaltonen Foundation, the European Union’s Horizon 2020 research and innovation program (under grant agreement HERCULES) as well as the Doctoral Program in Integrative Life Sciences, University of Helsinki.

Featured image: Ovarian cancer cells Photo: N/A

Provided by Karolinska Institute

Biology

Immune Cells in the Human Biliary System Mapped (Biology)

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Researchers at Karolinska Institutet have analysed and described in detail the immune cells residing in the human bile duct. The findings may pave the way for new treatment strategies against disorders of the bile duct, which are often linked to immunological processes. The study is published in the journal Science Translational Medicine.

Over the last decade, our understanding of the composition of immune cells across most tissues has increased immensely. However, the human biliary tract has remained one of few unexplored immunological niches because of difficulties in accessing this site. The biliary system, which includes the bile duct connecting the liver with the intestine, is an organ often affected by serious inflammatory and malignant diseases.

Dismal prognosis

Portrait of Niklas Björkström.
Niklas Björkström. Photo: Markus Marcetic

“Difficulties in studying this organ has hampered our understanding of biliary diseases, many of which are severe with dismal prognosis,” says Niklas Björkström, physician and immunology researcher at the Center for Infectious Medicine, the Department of Medicine, Huddinge, Karolinska Institutet, who led the study.

To overcome this, the researchers at Karolinska Institutet, in close collaboration with clinical scientists at the Karolinska University Hospital, employed a novel clinical examination method for retrieving and studying immune cells localised in the biliary system. With this method, they managed to retrieve immune cells from the bile duct of 125 patients and in detail characterise each of these immune cells.

The researchers compared immune cells from patients with primary sclerosing cholangitis (PSC), a severe inflammatory disease of the biliary system, with immune cells from non-inflammatory controls. PSC patients had a high infiltration of immune cells called neutrophils and T cells in their bile ducts that seemed to cooperate in causing an inflammatory environment.

Resource for future studies

“Our study sheds new light on the immunological processes involved in PSC,” says Niklas Björkström. “It also helps uncover the immunological niche of human bile ducts, which is a major step forward and will provide an important resource for future studies of the immune response in biliary disorders.”

The research was funded by the Swedish Research Council, the Swedish Cancer Society, the Swedish Foundation for Strategic Research, the Swedish Society for Medical Research, the Cancer Research Foundations of Radiumhemmet, Knut and Alice Wallenberg Foundation, the Novo Nordisk Foundation, the Center for Innovative Medicine at Karolinska Institutet, Region Stockholm, and Karolinska Institutet. The authors declare that there is no conflict of interest.

Publication

“A biliary immune landscape map of primary sclerosing cholangitis reveals a dominant network of neutrophils and tissue-resident T cells”. Christine L. Zimmer, Erik von Seth, Marcus Buggert, Otto Strauss, Laura Hertwig, Son Nguyen, Alicia Y. W. Wong, Chiara Zotter, Lena Berglin, Jakob Michaëlsson, Marcus Reuterwall Hansson, Urban Arnelo, Ernesto Sparrelid, Ewa C. S. Ellis, Johan D. Söderholm, Åsa V. Keita, Kristian Holm, Volkan Özenci, Johannes R. Hov Jeff E. Mold, Martin Cornillet, Andrea Ponzetta, Annika Bergquist, and Niklas K. Björkström. Science Translational Medicine, online 23 June, 2021, doi: 10.1126/scitranslmed.abb3107.

Featured image credit: Getty images

Provided by Karolinska Institute

Paleontology

New Evidence To Answer The Question ‘Who Exactly Were the Anglo-Saxons?’ (Paleontology)

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A new study from archaeologists at University of Sydney and Simon Fraser University in Vancouver, has provided important new evidence to answer the question “Who exactly were the Anglo-Saxons?”

New findings based on studying skeletal remains clearly indicates the Anglo-Saxons were a melting pot of people from both migrant and local cultural groups and not one homogenous group from Western Europe.

Professor Keith Dobney at the University of Sydney said the team’s results indicate that “the Anglo-Saxon kingdoms of early Medieval Britain were strikingly similar to contemporary Britain – full of people of different ancestries sharing a common language and culture”.

The Anglo-Saxon (or early medieval) period in England runs from the 5th-11th centuries AD. Early Anglo-Saxon dates from around 410-660 AD – with migration occurring throughout all but the final 100 years (ie 410-560AD).

Studying ancient skulls

Published in PLOS ONE, the collaborative study by Professor Dobney at University of Sydney and Dr Kimberly Plomp and Professor Mark Collard at Simon Fraser University in Vancouver, looked at the three-dimensional shape of the base of the skull.

“Previous studies by palaeoanthropologists have shown that the base of the human skull holds a shape signature that can be used to track relationships among human populations in a similar way to ancient DNA,” Dr Plomp said. “Based on this, we collected 3D data from suitably dated skeletal collections from Britain and Denmark, and then analysed the data to estimate the ancestry of the Anglo-Saxon individuals in the sample.”

The researchers found that between two-thirds and three-quarters of early Anglo-Saxon individuals were of continental European ancestry, while between a quarter and one-third were of local ancestry.

When they looked at skeletons dated to the Middle Anglo-Saxon period (several hundred years after the original migrants arrived), they found that 50 to 70 percent of the individuals were of local ancestry, while 30 to 50 percent were of continental European ancestry, which probably indicates a change in the rate of migration and/or local adoption of culture over time.

“These findings tell us that being Anglo-Saxon was more likely a matter of language and culture, not genetics,” Professor Collard said.

The debate about Anglo-Saxons

Although Anglo-Saxon origins can clearly be traced to a migration of Germanic-speaking people from mainland Europe between the 5th and 7th centuries AD, the number of individuals who settled in Britain is still contested, as is the nature of their relationship with the pre-existing inhabitants of the British Isles, most of whom were Romano-Celts.

The ongoing and unresolved argument is whether hordes of European invaders largely replaced the existing Romano-British inhabitants, or did smaller numbers of migrants settle and interact with the locals, who then rapidly adopted the new language and culture of the Anglo-Saxons?

“The reason for the ongoing confusion is the apparent contradiction between early historical texts (written sometime after the events that imply that the newcomers were both numerous and replaced the Romano-British population) and some recent biomolecular markers directly recovered from Anglo-Saxon skeletons that appears to suggest numbers of immigrants were few,” said Professor Dobney.

“Our new data sits at the interface of this debate and implies that early Anglo-Saxon society was a mix of both newcomers and immigrants and, instead of wholesale population replacement, a process of acculturation resulted in Anglo-Saxon language and culture being adopted wholesale by the local population.”

“It could be this new cultural package was attractive, filling a vacuum left at the end of the Roman occupation of Britain. Whatever the reason, it lit the fuse for the English nation we have today – still comprised of people of different origins who share the same language,” Professor Dobney said.

Featured image: The famous Anglo-Saxon Sutton Hoo helmet from about 625 CE, part of the British Museum collection. Photo: Elissa Blake/University of Sydney

Reference: Plomp KA, Dobney K, Collard M (2021) A 3D basicranial shape-based assessment of local and continental northwest European ancestry among 5th to 9th century CE Anglo-Saxons. PLoS ONE 16(6): e0252477. doi:10.1371/journal.pone.0252477

Provided by University of Sydney

Paleontology

3,000-year-old Shark Attack Victim Found by Oxford-led Researchers (Paleontology)

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Newspapers regularly carry stories of terrifying shark attacks, but in a paper published today, Oxford-led researchers reveal their discovery of a 3,000-year-old victim – attacked by a shark in the Seto Inland Sea of the Japanese archipelago.

The research in Journal of Archaeological Science: Reports, shows that this body is the earliest direct evidence for a shark attack on a human and an international research team has carefully recreated what happened – using a combination of archaeological science and forensic techniques.

The grim discovery of the victim was made by Oxford researchers, J. Alyssa White and Professor Rick Schulting, while investigating evidence for violent trauma on the skeletal remains of prehistoric hunter-gatherers at Kyoto University. They came upon No24, from the previously excavated site of Tsukumo, an adult male riddled with traumatic injuries.

‘We were initially flummoxed by what could have caused at least 790 deep, serrated injuries to this man,’ say the Oxford pair. ‘There were so many injuries and yet he was buried in the community burial ground, the Tsukumo Shell-mound cemetery site.’

They continue, ‘The injuries were mainly confined to the arms, legs, and front of the chest and abdomen. Through a process of elimination, we ruled out human conflict and more commonly-reported animal predators or scavengers.’

Since archaeological cases of shark reports are extremely rare, they turned to forensic shark attack cases for clues and worked with expert George Burgess, Director Emeritus of the Florida Program for Shark Research. And a reconstruction of the attack was put together by the international team.

The team concluded that the individual died more than 3,000 years ago, between 1370 to 1010 BC. The distribution of wounds strongly suggest the victim was alive at the time of attack; his left hand was sheared off, possibly a defence wound.

Individual No 24’s body had been recovered soon after the attack and buried with his people at the cemetery. Excavation records showed he was also missing his right leg and his left leg was placed on top of his body in an inverted position.

According to the pair, ‘Given the injuries, he was clearly the victim of a shark attack. The man may well have been fishing with companions at the time, since he was recovered quickly. And, based on the character and distribution of the tooth marks, the most likely species responsible was either a tiger or white shark.’

Co-author Dr Mark Hudson, a researcher with the Max Planck Institute, says, ‘The Neolithic people of Jomon Japan exploited a range of marine resources… It’s not clear if Tsukumo 24 was deliberately targeting sharks or if the shark was attracted by blood or bait from other fish. Either way, this find not only provides a new perspective on ancient Japan, but is also a rare example of archaeologists being able to reconstruct a dramatic episode in the life of a prehistoric community.’

Featured image: Original excavation photograph of Tsukumo No. 24, courtesy of the Laboratory of Physical Anthropology, Kyoto University. © Kyoto University

Notes for Editors

  • The paper can be seen here: https://www.sciencedirect.com/science/article/abs/pii/S2352409X21002777?dgcid=author
  • A novel method of 3D analysis in development by Alyssa White, John Pouncett, and Rick Schulting was used to visualise the wounds found, which can be explored at Tsukumo 24 BodyMap 3D.
  • Authors: J. Alyssa White, George H. Burgess, Masato Nakatsukasa, Mark J. Hudson, John Pouncett, Soichiro Kusaka, Minoru Yoneda, Yasuhiro Yamada, Rick Schulting

Provided by University of Oxford

Biology

Researchers Discover How To Reverse Cardiac Scarring And How This Could Treat Heart Failure (Biology)

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A healthy heart is a pliable, ever-moving organ. But under stress—from injury, cardiovascular disease, or aging—the heart thickens and stiffens in a process known as fibrosis, which involves diffuse scar-like tissue. Slowing or stopping fibrosis to treat and prevent heart failure has long been a goal of cardiologists.

Now, researchers at Gladstone Institutes have discovered a master switch for fibrosis in the heart. When the heart is under stress, they found, the gene MEOX1 is turned on in cells called fibroblasts, spurring fibrosis. Their new study, published in the journal Nature, suggests that blocking this gene could prevent fibrosis in the heart—and other organs that can similarly fail from stiffening over time.

“With these findings, we may have an entirely new way to stop that slow but steady progression of heart failure that affects 24 million people worldwide,” says Deepak Srivastava, MD, president and senior investigator at Gladstone and senior author of the study. “Right now, we don’t have any drugs that effectively prevent fibrosis.”

Deepak Srivastava, senior investigator at Gladstone Institutes
Deepak Srivastava and his team hope to identify a new approach to prevent the detrimental development of scar-like tissue in the heart and other organs. ©Gladstone Institutes

Fibroblasts are key to normal organ repair and integrity; they’re the most abundant cell in connective tissue and congregate at sites of bodily damage or disease. In many cases, their presence is beneficial. They help launch immune responses, mediate inflammation, and rebuild tissue. But in chronic disease, activated fibroblasts can continuously create scar tissue, impeding normal organ function.

Researchers knew that in mice with heart disease, blocking a class of proteins known as BET proteins slowed fibrosis and improved heart function, although it wasn’t clear which cell type in the heart was being affected. They also knew that BET proteins are needed throughout the body for many important functions, including normal immunity.

“To treat a heart failure patient with a BET inhibitor is a sledgehammer approach, because we might prevent fibrosis, but we’d likely also disrupt many other critical cellular functions throughout the body in the process,” says Srivastava, who is also a pediatric cardiologist and a professor in the Department of Pediatrics at UC San Francisco (UCSF). “Our hope was that if we could understand the precise mechanism through which BET works in the heart, we could home in on a narrower target with fewer side effects.”

Srivastava’s group studied mice who developed heart failure, and treated them daily with a BET inhibitor for 1 month. The researchers used single-cell RNA sequencing and single-cell epigenomics—which can reveal which genes in a cell are accessible and being turned on at any given time—to compare heart cells from mice before, during, and after the treatment, and correlate those results with heart function.

These technologies allowed the researchers to analyze thousands of cells at once, and separate them based on their specific cell type. Thanks to a close collaboration with the laboratory of Katie Pollard, PhD, at Gladstone, they developed new computational methods to learn from the vast amount of data generated by their analysis.

While the scientists didn’t find significant changes to heart muscle cells, they observed that the treatment induced striking changes in cardiac fibroblasts, which represent more than half the cells in the human heart.

In particular, the researchers discovered that the gene MEOX1 was highly active in the mice with heart failure and that its levels dramatically dropped when the mice were treated with the BET inhibitor. Moreover, the levels of MEOX1 correlated with activation of the fibroblasts; when the gene was switched on, the fibroblasts were better at making scar tissue. In fact, MEOX1 seemed to be a “master regulator” of fibroblast activation, controlling thousands of other genes that contribute to fibrosis.

“MEOX1 is a gene known to be important in early development, but not much was known about it in adult disease, so our findings were quite surprising,” says Michael Alexanian, PhD, a Gladstone postdoctoral scholar and first author of the new study.

Michael Alexanian, postdoc at Gladstone Institutes
Michael Alexanian, the study’s first author, showed that deleting a small part of DNA blocks the activation of fibroblasts. © Gladstone Institutes

The findings point to the precise part of the DNA, regulated by BET, that is responsible for MEOX1 to be turned on in disease states. Using CRISPR genome-editing technology, the scientists showed that deleting this small part of the DNA prevented MEOX1 from being activated, even under stress.

The team went on to show that blocking MEOX1 from being switched on had the same effects as a BET inhibitor—it blocks the activation of fibroblasts. The researchers also studied other organs that commonly become fibrotic with disease, and found that cellular stress led to higher levels of MEOX1 in human lung, liver, and kidney fibroblasts.

“Fibrosis is much broader than just the heart; it affects many other organs,” says Srivastava. “We hope this discovery provides an avenue to slow down or stop fibrosis in many settings.”

More studies are needed to show whether blocking MEOX1 could have therapeutic value in humans. Srivastava and his colleagues are now conducting additional studies to better understand the long-term role of MEOX1 in heart disease and heart failure.

“In a coordinated effort to design novel therapies for heart failure, researchers are looking for molecular clues to use as therapeutic targets,” says Bishow Adhikari, PhD, a program officer in the heart failure and arrhythmias branch, located within the Division of Cardiovascular Sciences at the National Heart, Lung, and Blood Institute. “These findings are highly informative and bring researchers closer to advancing new therapeutic strategies to better predict and treat heart disease.”

About the Study

The paper “A Transcriptional Switch Governs Fibroblast Activation in Heart Disease” was published by the journal Nature on June 23, 2021.

Other authors are: Pawel Przytycki, Arun Padmanabhan, Lin Ye, Bárbara Gonzàlez Teràn, Ana Catarina Silva, Qiming Duan, Sanjeev Ranade, Franco Felix, Clara Yougna Lee, Nandhini Sadagopan, Angelo Pelonero, Yu Huang, Casey Gifford, and Saptarsi Haldar of Gladstone; Rudi Micheletti and Michael Rosenfeld of UC San Diego; Joshua Travers and Timothy McKinsey of University of Colorado; Ricardo Linares-Saldana, Li Li and Rajan Jain of University of Pennsylvania; and Gaia Andreoletti of UCSF.

The work at Gladstone was supported by the Swiss National Science Foundation, the National Institutes of Health (P01 HL098707, HL098179, R01 HL127240, P01 HL146366, R01 HL057181, R01 HL015100, C06 RR018928), the San Simeon Fund, the Tobacco‐Related Disease Research Program, A.P. Giannini Foundation, Michael Antonov Charitable Foundation Inc., Sarnoff Cardiovascular Research Foundation, the American Heart Association, the Roddenberry Foundation, the L.K. Whittier Foundation, Dario and Irina Sattui, and the Younger Family Fund.

Featured image: Michael Alexanian, a postdoc in the Srivastava Lab, helped discover a gene that could prevent fibrosis in the heart. © Gladstone Institutes

Provided by Gladstone Institutes

Medicine

Drug Doubles Down on Bone Cancer, Metastasis (Medicine)

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Rice, Baylor’s ‘BonTarg’ combines breast cancer drug with bone-targeting antibody

Bone cancer is hard to treat and prone to metastasis. Research teams at Rice University and Baylor College of Medicine have a new strategy to attack it.

Chemist Han Xiao at Rice and biologist Xiang Zhang at Baylor and their labs have developed an antibody conjugate called BonTarg that delivers drugs to bone tumors and inhibits metastasis.

Their open-access study, which appears in Science Advances, shows how Xiao’s pClick technology can be used to link bone-targeting antibodies and therapeutic molecules.

Scientists are using pClick conjugation to create therapeutic antibodies that target bone cancers. The conjugate incorporates bisphosphonate molecules that bind to the bone hydroxyapatite matrix. Courtesy of Baylor College of Medicine/Rice University

In experiments, they used pClick to couple a molecule used to treat osteoporosis, alendronate, with the HER2-targeting antibody trastuzumab used to treat breast cancer and found it significantly enhanced the concentration of the antibody at tumor sites.

They reported the combination also inhibited secondary metastasis from infected organs seeded by bone tumors.

“Bone cancer is really challenging to treat, and clinical trials of different treatments have been disappointing for people with bone metastasis,” said Xiao, who joined Rice in 2017 with funding from the Cancer Prevention and Research Institute of Texas (CPRIT). “We feel our strategy is a real game changer.”

“Getting effective concentrations of drugs to bone tumors has been challenging because bones are hard, their networks of blood vessels is limited and drugs have tended to attach to adjacent healthy tissues,” Zhang said.

The new strategy employs bisphosphonates, a class of drugs typically used to treat osteoporosis. Bisphosphonates have a high binding affinity for hydroxyapatite, the main component of hard bone, and help overcome physical and biological barriers in the bone microenvironment.

They’re also amenable to binding with drugs through pClick, which uses a cross-linker to snap to specific sites on antibodies without having to re-engineer them with harmful chemicals, enzymes or ultraviolet light.

MicroCT scans of rodents show those treated with the conjugate of trastuzumab and alendronate (far right), created at Rice University and Baylor College of Medicine, fared far better than those treated with phosphate-buffered saline (PBS) or alendronate (ALN) or trastuzumab (Tras) alone 82 days after tumor implantation. (Credit: Baylor College of Medicine/Rice University)
MicroCT scans of rodents show those treated with the conjugate of trastuzumab and alendronate (far right), created at Rice University and Baylor College of Medicine, fared far better than those treated with phosphate-buffered saline (PBS) or alendronate (ALN) or trastuzumab (Tras) alone 82 days after tumor implantation. Courtesy of Baylor College of Medicine/Rice University

The result is a molecule that seeks out bone tumors and stays put, giving the drug time to kill tumor cells. It helps that bisphosphonate molecules prefer acidic sites like bone tumors, keeping the drug concentration higher there than in surrounding healthy tissue.

The researchers chose breast cancer drugs because while many recover from the disease, 20 to 40% of breast cancer survivors eventually suffer metastases to distant organs, with metastasis to bone occurring in about 70% of these cases, significantly increasing mortality, they said.

While chemotherapy, hormone and radiation therapy used to treat women with bone metastatic breast cancers can shrink or slow bone metastasis, they usually do not eliminate the metastases, Xiao said.

“Bone is kind of a fertile soil for cancer cell,” Xiao said. “If a cancer cell reaches it, then it has a really good chance to grow and to further migrate, for example to the brain, the heart, the liver or to other tissues. That’s a really bad situation for a patient.”

Xiao hopes to get the compound into a clinical trial, and sees potential for custom conjugates that treat other tumors prone to metastasis, including prostate cancer.

Postdoctoral researchers Zeru Tian of Rice and Ling Wu of Baylor are co-lead authors of the paper. Co-authors are graduate students Chenfei Yu, Yuda Chen, Axel Loredo and Kuan-Lin Wu and postdoctoral researcher Lushun Wang of Rice; and postdoctoral fellows Zhan Xu, Igor Bado and Weijie Zhang and instructor Hai Wang of Baylor.

Xiang Zhang, left, at Baylor College of Medicine, and Han Xiao at Rice University have developed an antibody conjugate called BonTarg that delivers drugs to bone tumors and inhibits metastasis. (Credit: Rice University/Baylor College of Medicine)

Xiao is the Norman Hackerman-Welch Young Investigator, the Cancer Prevention and Research Institute of Texas (CPRIT) Scholar in Cancer Research and an assistant professor of chemistry, bioengineering and biosciences. Zhang is the William T. Butler, M.D., Endowed Chair for Distinguished Faculty, McNair Scholar, associate director of the Lester and Sue Smith Breast Center, professor of molecular and cellular biology and member of the Dan L Duncan Comprehensive Cancer Center.

The research was supported by CPRIT, the National Institutes of Health, the Robert A. Welch Foundation, the U.S. Department of Defense, the John S. Dunn Foundation, the Hamill Foundation, the Breast Cancer Research Foundation and the McNair Medical Institute.

Read the abstract at https://advances.sciencemag.org/lookup/doi/10.1126/sciadv.abf2051.

Provided by Rice University

Neuroscience

New Study Finds Abnormal Response to Cellular Stress is Associated With Huntington’s Disease (Neuroscience)

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A new University of California, Irvine-led study finds that the persistence of a marker of chronic cellular stress, previously associated with neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), also takes place in the brains of Huntington’s disease (HD) patients.

Chronic cellular stress results in the abnormal accumulation of stress granules (SGs), which are clumps of protein and RNAs that gather in the cell. Prior to this study, published in the Journal of Clinical Investigation, it was not known if these types of granules were a pathological feature of HD, an inherited and progressive neurodegenerative disorder that typically strikes in the prime of life.

In addition to identifying SGs as a pathological feature of HD, researchers made several other discoveries including that extracellular vesicles, which float in cerebrospinal fluid (CSF) and act as a messaging system between cells in the brain, can potentially alter the behavior of other cells and impact the abnormal accumulation of the granules. They also found that TAR DNA-binding protein 43 (TDP43) is mislocalized, which has emerged as a critical feature of multiple neurodegenerative diseases.

“We were initially interested in whether the profile of these messages could serve as a biomarker for HD and investigated whether the vesicles from HD patients contain messages that are different from those of unaffected individuals,” said first author Isabella I. Sanchez, PhD, from the Thompson Laboratory at UCI School of Medicine.

Researchers found that the CSF of HD patients carried messages in the form of small non-coding RNAs (miRNAs) that did were predicted to alter the production of proteins that are indispensable for SG formation. They soon identified a key player in SG dynamics, GTPase-activating protein-binding protein 1 (G3BP1), as a predicted target.

“This finding regarding the miRNAs was very exciting, as we had simultaneously started investigations to characterize SGs in HD brain tissues.  SGs can be very difficult to detect in brain tissues, and it just so happened that we had narrowed down the adequate conditions and were ready to being characterizing G3BP1 SGs in HD mouse and HD patient brains,” said Leslie M. Thompson, PhD, Donald Bren and UCI Chancellor’s professor in the Departments of Psychiatry & Human Behavior and Biological Chemistry at the UCI School of Medicine, and Neurobiology and Behavior at the UCI School of Biological Sciences.   

While SG formation is a normal physiological process that enables cells to overcome stressful conditions, the SG pathology in HD may result from an accumulation G3BP1 SGs that initially served a protective function, but develop into hyper-stable structures over time.

“We hope that our findings will inform future studies aimed at understanding how SG accumulation affects HD progression, and whether targeting SG pathology is a viable therapeutic avenue in the fight against HD,” said Robert Spitale, PhD, professor in the Department of Pharmaceutical Sciences and also a lead author of the study.

This research was supported in part by grants from the Medical Research Council, CHDI Foundation, the National Institutes of Health, Chan Zuckerberg Initiative, National Center for Research Resources, National Center for Advancing Translational Sciences, and the UCI Institute for Clinical & Translational Science.

Featured image: Shown is a surface rendering of G3BP1 granules (in green) detected by immunofluorescence in the HD mouse model cortex. © UCI School of Medicine

Reference: Isabella I. Sanchez, … , Robert C. Spitale, Leslie M. Thompson, “Huntington’s disease mice and human brain tissue exhibit increased G3BP1 granules and TDP43 mislocalization”, J Clin Invest. 2021;131(12):e140723. https://doi.org/10.1172/JCI140723.

Provided by UCI School of Medicine

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