Enhanced Scorpion Venom Molecules Can Be Used to Treat Chagas Disease (Medicine)

Brazilian researchers tested the antichagasic properties of VmCT1, obtained from the venom of Vaejovis mexicanus, a scorpion harmless to humans, and synthesized novel analogs to redesign the native molecule.

Animal toxins are research targets owing to their therapeutic and biotechnological potential. Researchers at the Federal University of the ABC (UFABC), Federal University of São Paulo (UNIFESP) and Federal University of Ceará (UFC) in Brazil have discovered that VmCT1, an antimicrobial peptide isolated from the venom of the scorpion Vaejovis mexicanus, and its analogs kill Trypanosoma cruzi, the parasite that causes Chagas disease. Previous research has demonstrated VmCT1’s potential against Gram-positive and Gram-negative bacteria, as well as tumor cells and other protozoans.

“VmCT1 contains 13 amino acid residues and displayed good selectivity and high potency against all three developmental phases of the protozoan Trypanosoma cruzi, the etiological agent of Chagas disease,” said Vani Xavier de Oliveira Junior, a professor at UFABC’s Center for Natural and Human Sciences and principal investigator for the study.

An article on the study is published in Parasitology, a journal owned by Cambridge University Press, and highlighted in the Cambridge Core Blog’s Paper of the Month column. The study was supported by FAPESP.

“Not all species of scorpion are dangerous to humans,” Oliveira said. “Venom from the genus Vaejovis affects only insects. On the other hand, it has potential therapeutic value because it contains several effective antimicrobial peptides, whose main role is defending the host.”

Chagas is considered a neglected disease by the World Health Organization (WHO). It is endemic in several countries, affecting some 8 million people worldwide and killing around 10,000 per year.

“Treatment is currently available only in the form of two drugs that have severe side-effects and work only in the acute phase, when the patient may have few or no symptoms of the disease,” Oliveira said. “This is why the search for novel medications is so important. Antimicrobial peptides are especially promising.”

The researchers assessed the trypanocidal effect of VmCT1 and synthesized novel analogs with arginine substitutions in key positions to boost their biological action. Arginine is a positively charged amino acid and helps disrupt the parasite’s membrane.

The results showed that the natural peptide was effective against all three phases of the parasite’s development, while one of the analogs displayed both enhanced biological activity and better selectivity.

“In addition, we discovered that changes to physicochemical parameters influenced activity in the biological model, demonstrating that this kind of peptide reengineering can deliver more effective analogs than the native peptide,” Oliveira said.

The selectivity of antimicrobial peptides to the pathogen relates to their cationicity, a trait that influences peptide-membrane interaction. According to the authors, the analogs with the positively charged amino acid arginine are more likely to interact with phospholipids in the membranes of microorganisms, promoting destabilization, disruption and/or permeabilization of the membranes.

“VmCT1 comprises a small peptide sequence, which helps obtain chemically altered molecules quickly and facilitates modulation between its biological activity and toxicity in human cells,” said Cibele Nicolaski Pedron, a researcher at UFABC and first author of the article.

The trypanocidal activity was due to the formation of pores, evidenced by electron scanning microscopy. The damage done to the membranes by the peptides was significant, causing the death of parasites at levels not toxic to host cells.

“Our results demonstrate that VmCT1 and its arginine-substituted analogs are promising antiparasitic molecules that offer new prospects for the treatment of Chagas disease,” said Alice Martins, a researcher at UFC and a co-author of the article.

The technological products developed in the study were registered with the National Industrial Property Institute (INPI), Brazil’s patent and trademark office.

Reference: Pedron, C., Freire, K., Torres, M., Lima, D., Monteiro, M., Menezes, R., . . . Oliveira, V. (2020). Arg-substituted VmCT1 analogs reveals promising candidate for the development of new antichagasic agent. Parasitology, 147(14), 1810-1818. doi:10.1017/S0031182020001882 https://www.cambridge.org/core/journals/parasitology/article/argsubstituted-vmct1-analogs-reveals-promising-candidate-for-the-development-of-new-antichagasic-agent/D53293DF66E8B5064A069A8587418095

Provided by FAPESP

About São Paulo Research Foundation (FAPESP)

The São Paulo Research Foundation (FAPESP) is a public institution with the mission of supporting scientific research in all fields of knowledge by awarding scholarships, fellowships and grants to investigators linked with higher education and research institutions in the State of São Paulo, Brazil. FAPESP is aware that the very best research can only be done by working with the best researchers internationally. Therefore, it has established partnerships with funding agencies, higher education, private companies, and research organizations in other countries known for the quality of their research and has been encouraging scientists funded by its grants to further develop their international collaboration. You can learn more about FAPESP at http://www.fapesp.br/en and visit FAPESP news agency at http://www.agencia.fapesp.br/en to keep updated with the latest scientific breakthroughs FAPESP helps achieve through its many programs, awards and research centers. You may also subscribe to FAPESP news agency at http://agencia.fapesp.br/subscribe.

Scientists Discover a New Type of Brain Cell That Could Help Detect Distance (Neuroscience)

The existence of GPS-like brain cells, which can store maps of the places we’ve been, like our kitchen or holiday destination, was already widely known, but this discovery shows there is also a type of brain cell sensitive to the distance and direction of objects that can store their locations on these maps.

Dr. Steven Poulter and Dr. Colin Lever in the lab discovering the cells. © Dr. Steven Poulter and Dr. Colin Lever

The research, led by Dr Steven Poulter and Dr Colin Lever from Durham University, and co-directed by Dr Thomas Wills from the University of Central London (UCL), found that Vector Trace cells can track how far we have travelled and remember where things are, which are added to our memory map of the places we have been.

Dr Steven Poulter said: “The discovery of Vector Trace cells is particularly important as the area of the brain they are found in is one of the first to be attacked by brain disorders such as Alzheimer’s disease, which could explain why a common symptom and key early ‘warning sign’ is the losing or misplacement of objects.”

Dr Lever added: “It looks like Vector Trace cells connect to creative brain networks which help us to plan our actions and imagine complex scenarios in our mind’s eye. Vector trace cells acting together likely allow us to recreate the spatial relationships between ourselves and objects, and between the objects in a scene, even when those objects are not directly visible to us.”

Brain cells that make up the biological equivalent of a satellite-navigation system were first discovered <> by Professors John O’Keefe, Edvard Moser, May-Britt Moser. Their discovery shed light on one of neurosciences great mysteries – how we know where we are in space – and won them the 2014 Nobel Prize in Medicine.

Speaking about the discovery, Professor John O’Keefe said: “I’m very impressed. Not only have they discovered a new type of brain cell, the Vector Trace cell, but their analysis of its properties is exhaustive and compelling. This discovery sheds considerable light on this important but enigmatic structure of the brain, supporting the idea that it is indeed the memory system we have always believed it to be.”

Professor Lord Robert Winston added: “This fascinating work on Vector Trace cells uncovers further levels of our memory, so often lost with brain damage and ageing. This discovery gives a possible insight into certain kinds of dementia which are now of massive importance.

He added: “The idea that loss or change of such cells might be an early biomarker of disease could lead to earlier diagnosis and more effective therapies for one of the most intractable medical conditions.”

Provided by Durham University

A “Cosmic Microscope” Reveals The Origin Of Galactic Winds Produced By Supermassive Black Holes (Astronomy / Cosmology)

By studying a sample of distant galaxies, whose light reaches us from a cosmic epoch when the Universe was just three billion years old, a team of researchers led by Giustina Vietri of the Italian National Institute for Astrophysics (INAF) has followed the winds blowing in “active” galaxies down to only a few light-years from the supermassive black holes that sit in the galactic cores. The new study demonstrates how these winds, which travel as fast as millions of kilometres per hour, have the potential to influence interstellar gas on scales of tens of thousands light-years.

Dust torus around SMBH © ESA / Hubble

The majority of supermassive black holes lurking in galaxies, like the one at the centre of our own Milky Way, are harmless and swallow at most the occasional star or gas cloud that dare venture too close. A small percentage, however, is in great turmoil, devouring the surrounding matter at high pace via an accretion disc that heats up and emits radiation across the electromagnetic spectrum. It is from these signals that it is possible to recognise “active” galaxies, hosting such frenzied black holes, in astronomical observations.

Not even the most “voracious” black holes, however, are capable of eating all the material in their surroundings, triggering enormous winds that throw away part of this material and can propagate over galactic scales. Astrophysicists have been debating for years about the importance of such winds and their possible effects on the evolution of the host galaxies via feedback mechanisms, which might have the potential to regulate both the growth of the central black hole and the formation of new stars.

“It’s a topic of great importance to understand how the Universe has evolved”, comments Giustina Vietri from INAF in Milan, first author of a new study analysing the effect of such winds on different scales within galaxies, for the first time using a representative sample of active galaxies. “In this study we tried to shed new light on one of the currently most debated issues: the link between the central supermassive black holes and their host galaxies”.

The results, published in Astronomy & Astrophysics, are part of the SUPER project (A SINFONI Survey for Unveiling the Physics and Effect of Radiative feedback), which has already produced two papers authored by the same team of researchers. The project was created with the aim of studying the release of gas from galactic centres using the SINFONI instrument on ESO’s Very Large Telescope, in Chile.

“SINFONI is an integral-field spectrograph operating in the near-infrared and exploiting adaptive optics to gather high-resolution spectra of extended sources”, explains Vincenzo Mainieri from ESO, principal investigator of the SUPER project and co-author of the new study. “With respect to previous instruments used for spectroscopic surveys of active galaxies, SINFONI enables us to spatially resolve the gas”.

Thanks to the data obtained with SINFONI, the team has analysed a representative sample of 21 active galaxies, studying the connection between black holes and their host galaxies, for the first time, in a systematic fashion. This means they did not have to select galaxies where the presence of winds was already known. The observations have revealed the presence of galactic winds in all examined sources. The result demonstrates how prevalent these phenomena are in the cosmic epoch to which these galaxies belong, when our 13.8 billion-year old Universe was only 3 billion years of age.

“These winds, travelling at speeds between 3 and 7 million km/h, reach out to twenty thousand light-years from the centre of their host galaxies”, adds co-author Michele Perna from INAF in Florence and Centro de Astrobiología in Madrid, Spain.

The researchers then followed the winds all the way to their origin, in the vicinity of the monster black holes, by making use of an astronomical “microscope” – analysing optical spectra of these galaxies available from the archives.

“The lines emitted by ionised carbon atoms, which we see in spectra from the Sloan Digital Sky Survey, are produced only a few light-years away from the black hole, revealing how the winds of ionised material discovered with SINFONI are also present on these relatively small scales, in the heart of galaxies”, explains Vietri. “By doing so, we could link for the first time the presence of outflows from the proximity of the black hole to galaxy scales”.

The results show how the winds observed at small distances from the central black hole depend on its properties – such as the accretion rate or the brightness of the galactic core, which is in turn produced by the black hole’s activity. Furthermore, these winds might have the potential to influence gas all the way to the outskirts of their host galaxies. In the future, the researchers will try to trace these winds on even larger scales to keep studying the influence that black holes may exert on the evolution of galaxies.

The study is published in Astronomy & Astrophysics in the paper “SUPER III. Broad Line Region properties of AGN at z∼2” by G. Vietri, V. Mainieri, D. Kakkad, H. Netzer, M. Perna, C. Circosta, C. M. Harrison, L. Zappacosta, B. Husemann, P. Padovani, M. Bischetti, A. Bongiorno, M. Brusa, S. Carniani, C. Cicone, A. Comastri, G. Cresci, C. Feruglio, F. Fiore, G. Lanzuisi, F. Mannucci, A. Marconi, E. Piconcelli, A. Puglisi, M. Salvato, M. Schramm, A. Schulze, J. Scholtz, C. Vignali, G. Zamorani.

Provided by INAF

CRISPR Helps Researchers Uncover How Corals Adjust To Warming Oceans (Biology)

The revolutionary, Nobel Prize-winning technology can be deployed to guide conservation efforts for fragile reef ecosystems.

The CRISPR/Cas9 genome editing system can help scientists understand, and possibly improve, how corals respond to the environmental stresses of climate change. Work led by Phillip Cleves–who joined Carnegie’s Department of Embryology this fall–details how the revolutionary, Nobel Prize-winning technology can be deployed to guide conservation efforts for fragile reef ecosystems.

Coral © wikipedia

Cleves’ research team’s findings were recently published in two papers in the Proceedings of the National Academy of Sciences.

Corals are marine invertebrates that build extensive calcium carbonate skeletons from which reefs are constructed. But this architecture is only possible because of a mutually beneficial relationship between the coral and various species of single-celled algae that live inside individual coral cells. These algae convert the Sun’s energy into food using a process called photosynthesis and they share some of the nutrients they produce with their coral hosts–kind of like paying rent.

Coral reefs have great ecological, economic, and aesthetic value. Many communities depend on them for food and tourism. However, human activity is putting strain on coral reefs including warming oceans, pollution, and acidification and that affects this symbiotic relationship.

“In particular, increasing ocean temperatures can cause coral to lose their algae, a phenomenon called bleaching, because the coral takes on a ghostly white look in the absence of the algae’s pigment,” Cleves explained. “Without the nutrients provided by photosynthesis, the coral can die of starvation.”

In 2018, Cleves headed up the team that demonstrated the first use of the CRISPR/Cas9 genome editing on coral. Now, his teams used CRISPR/Cas9 to identify a gene responsible for regulating coral’s response to heat stress.

Working first in the anemone Aiptasia, one team–including Stanford University’s Cory Krediet, Erik Lehnert, Masayuki Onishi, and John Pringle–identified a protein, called Heat Shock Factor 1 (HSF1), which activates many genes associated with the response to heat stress. Anemones are close coral relatives that have similar symbiotic relationships with photosynthetic algae, but they grow faster and are easier to study. These traits make Aiptasia a powerful model system to study coral biology in the lab.

Then another Cleves-led team–including Stanford University’s Amanda Tinoco and John Pringle, Queensland University of Technology’s Jacob Bradford and Dimitri Perrin, and Line Bay of the Australian Institute of Marine Science (AIMS)–used CRISPR/Cas9 to create mutations in the gene that encodes HSF1 in the coral Acropora millepora, demonstrating its importance for coping with a warming environment. Without a functioning HSF1 protein, the coral died rapidly when the surrounding water temperature increased.

“Understanding the genetic traits of heat tolerance of corals holds the key to understanding not only how corals will respond to climate change naturally but also balancing the benefits, opportunities and risks of novel management tools,” said Bay, who is the AIMS principal research scientist and head of its Reef Recovery, Restoration and Adaptation team.

Added Cleves: “Our work further demonstrates how CRISPR/Cas9 can be used to elucidate aspects of coral physiology that can be used to guide conservation. This time we focused on one particular heat tolerance gene, but there are so many more mechanisms to reveal in order to truly understand coral biology and apply this knowledge to protecting these important communities.”

Reference: Phillip A. Cleves, Amanda I. Tinoco, Jacob Bradford, Dimitri Perrin, Line K. Bay, John R. Pringle, “Reduced thermal tolerance in a coral carrying CRISPR-induced mutations in the gene for a heat-shock transcription factor”, Proceedings of the National Academy of Sciences Nov 2020, 117 (46) 28899-28905; DOI: 10.1073/pnas.1920779117 https://www.pnas.org/content/117/46/28899

Provided by Carnegie Institute for Science

How Nearby Galaxies Form Their Stars? (Astronomy)

How stars form in galaxies remains a major open question in astrophysics. A new UZH study sheds new light on this topic with the help of a data-driven re-analysis of observational measurements. The star-formation activity of typical, nearby galaxies is found to scale proportionally with the amount of gas present in these galaxies. This points to the net gas supply from cosmic distances as the main driver of galactic star formation.

Stars (white) form throughout the gas disk. Figure 1 shows a visualization of gas in and around a Milky-Way-like galaxy (center) in today’s Universe as predicted by a cosmological simulation run by the author. Dense, atomic and molecular hydrogen typically forms an extended disk, here seen in bluish-purple at the center of the image. Stars (white) form throughout the gas disk. Additional star formation may take place in satellite galaxies, here seen at the top right and bottom left positions. Hot, low density gas (green and red hues) can be found at large distances, out to the edge of the dark matter halo surrounding the main galaxy (white circle). The image also shows a large number of dark matter substructures (purple) most of which are devoid of gas and stars. (Illustration: Robert Feldmann)

Stars are born in dense clouds of molecular hydrogen gas that permeates interstellar space of most galaxies. While the physics of star formation is complex, recent years have seen substantial progress towards understanding how stars form in a galactic environment. What ultimately determines the level of star formation in galaxies, however, remains an open question.

In principle, two main factors influence the star formation activity: The amount of molecular gas that is present in galaxies and the timescale over which the gas reservoir is depleted by converting it into stars. While the gas mass of galaxies is regulated by a competition between gas inflows, outflows and consumption, the physics of the gas-to-star conversion is currently not well understood. Given its potentially critical role, many efforts have been undertaken to determine the gas depletion timescale observationally. However, these efforts resulted in conflicting findings partly because of the challenge in measuring gas masses reliably given current detection limits.

Typical star formation is linked to the overall gas reservoir

The present study from the Institute for Computational Science of the University of Zurich uses a new statistical method based on Bayesian modeling to properly account for galaxies with undetected amounts of molecular or atomic hydrogen to minimize observational bias. This new analysis reveals that, in typical star-forming galaxies, molecular and atomic hydrogen are converted into stars over approximately constant timescales of 1 and 10 billion years, respectively. However, extremely active galaxies (“starbursts”) are found to have much shorter gas depletion timescales.

“These findings suggest that star formation is indeed directly linked to the overall gas reservoir and thus set by the rate at which gas enters or leaves a galaxy,” says Robert Feldmann, professor at the Center for Theoretical Astrophysics and Cosmology. In contrast, the dramatically higher star-formation activity of starbursts likely has a different physical origin, such as galaxy interactions or instabilities in galactic disks.

Far galaxies across cosmic history

This analysis is based on observational data of nearby galaxies. Observations with the Atacama Large Millimeter/Submillimeter Array, the Square Kilometer Array and other observatories promise to probe the gas content of large numbers of galaxies across cosmic history. It will be paramount to continue the development of statistical and data-science methods to accurately extract the physical content from these new observations and to fully uncover the mysteries of star formation in galaxies.

Reference: Feldmann, R. The link between star formation and gas in nearby galaxies. Commun Phys 3, 226 (2020). https://www.nature.com/articles/s42005-020-00493-0 https://doi.org/10.1038/s42005-020-00493-0

Provided by University of Zurich

Scientists Complete Yearlong Pulsar Timing Study After Reviving Long-dormant Radio Telescopes (Astronomy)

While the scientific community grapples with the loss of the Arecibo radio telescope, astronomers who recently revived a long-dormant radio telescope array in Argentina hope it can help modestly compensate for the work Arecibo did in pulsar timing. Last year, scientists at Rochester Institute of Technology and the Instituto Argentino de Radioastronomía (IAR) began a pulsar timing study using two upgraded radio telescopes in Argentina that previously lay unused for 15 years.

Scientists from RIT and IAR just completed a yearlong pulsar timing study using two upgraded radio telescopes in Argentina that previously lay unused for 15 years. The results will be published in ‘The Astrophysical Journal.’ © RIT

The scientists are releasing observations from the first year in a new study to be published in The Astrophysical Journal. Over the course of the year, they studied the bright millisecond pulsar J0437−4715. Pulsars are rapidly rotating neutron stars with intense magnetic fields that regularly emit radio waves, which scientists study to look for gravitational waves caused by the mergers of supermassive black holes.

Professor Carlos Lousto, a member of RIT’s School of Mathematical Sciences and the Center for Computational Relativity and Gravitation (CCRG), said the first year of observations proved to be very accurate and provided some bounds to gravitational waves, which can help increase the sensitivity of existing pulsar timing arrays. He said that over the course of the next year they plan to study a younger, less stable pulsar that is more prone to glitches. He hopes to leverage machine learning and artificial intelligence to better understand the individual pulses emitted by pulsars and predict when glitches occur.

“Every second of observation has 11 pulses and we have thousands of hours of observation, so it is a lot of data,” said Lousto. “What we hope to accomplish is analogous to monitoring the heartbeat one by one to learn to predict when someone is going to have a heart attack.”

Lousto said Ph.D. students from RIT’s programs in astrophysical sciences and technology, mathematical modeling, and computer science are at the forefront of the analysis. RIT has a remote station called the Pulsar Monitoring in Argentina Data Enabling Network (PuMA-DEN) to control the radio telescopes and store the data collected. He said the opportunities presented by the collaboration are important for the students from the College of Science and Golisano College of Computing and Information Sciences because “the careers in astronomy are changing very quickly, so you have to keep up with new technology and new ideas.”

In the longer term, Lousto said RIT and IAR are seeking out other radio telescopes that can be upgraded for pulsar timing studies, further filling the gap left behind by Arecibo. RIT and IAR’s observations seek to contribute to the larger efforts of the North American Nanohertz Observatory for Gravitation Waves (NANOGrav) and the International Pulsar Timing Array, an collaboration of scientists working to detect and study the impact of low frequency gravitational waves passing between the pulsars and the Earth.

For more information, you can read the study that will be published in The Astrophysical Journal on the arXiv preprint server.

Provided by Rochester Institute of Technology

Moffitt Researchers Discover Potential New Drug Target to Treat Cutaneous T Cell Lymphoma (Medicine)

Cutaneous T cell lymphomas (CTCLs) are a group of non-Hodgkin lymphomas that develop from T cells and mainly impact the skin with painful lesions. The two main subtypes of CTCL are mycosis fungoides and Sézary syndrome. CTCLs are extremely rare, with approximately six cases per 1 million people each year. It is unclear how CTCL develops, and unfortunately there are limited treatment options and no cure.

Moffitt Cancer Center treats approximately 16% of CTCL patients nationwide. In order to improve their understanding of how CTCL develops in hopes of developing new therapies, a team of Moffitt immunologists and hematologists, including Jose Conejo-Garcia, Ph.D., Javier Pinilla-Ibarz,, M.D., Ph.D. and Lubomir Sokol, M.D., Ph.D., conducted a series of studies. In an article published in The Journal of Clinical Investigation, they demonstrate that decreased expression of the protein SATB1 contributes to CTCL development and that drugs that cause SATB1 to become re-expressed may be potential treatment options for this disease.

The protein SATB1 plays an important role in cell death, proliferation and invasion, and has also been shown to be involved in the processes that control T cells differentiations. Recently, it was reported that mycosis fungoides is associated with lower levels of SATB1, suggesting that it may play an important role in the development of this disease.

To understand how SATB1 contributes to CTCL, Moffitt researchers created a mouse model that lacked SATB1 in combination with overexpression of NOTCH1, which is known to be involved in the development of CTCL. The mice developed enlarged spleens and livers, swollen lymph nodes, a high level of T cells and lived for a significantly shorter time than control mice. When the researchers examined the skin of the mice that were missing SATB1, they discovered characteristics that were similar to CTCL, suggesting that loss of SATB1 cooperates with NOTCH1 to promote CTCL development. The researchers confirmed these observations by showing that T cells from patients with Sézary syndrome have significantly lower levels of SATB1 than cells from healthy donors.

The researchers wanted to determine mechanistically how loss of SATB1 contributes to the development of CTCL in mice by assessing signaling pathways that were activated both upstream and downstream of SATB1. They performed a series of laboratory experiments to show SATB1 regulated the downstream protein STAT5 and other protein chemical receptors in T cells that cause them to expand in number.

Next, the researchers focused on upstream processes to determine how SATB1 loss occurs in patients’ samples. They discovered that a process called epigenetic regulation plays an important role in this loss. Specifically, they showed that DNA regulatory proteins called histones become methylated, which results in loss of SATB1 expression. They also discovered that drugs that prevent this methylation cause SATB1 to become re-expressed. These methylation inhibitors also prevented the growth of Sézary syndrome cells more effectively than the drug romidepsin, which is commonly used to treat CTCL patients. These observations suggest that drugs that target these methylation processes may be viable options to treat CTCL patients.

The researchers hope that their preclinical studies will eventually lead to clinical trials of methylation inhibitors in CTCL patients. “Our results offer new insight into the pathophysiology of CTCL, as well as a mechanistic rationale for targeting histone methyltransferases to abrogate malignant expansion and skin homing in advanced CTCL patients,” said Carly Harro, study first author and student in Moffitt’s Cancer Biology Ph.D. Program.

This study was supported by the National Institutes of Health (R01CA240434, R01CA157664, R01CA124515, T32CA009140, U01CA200495, P30CA076292) and the American Cancer Society (PF-18-041-1-LIB).

Reference: Carly M. Harro, … , Lubomir Sokol, Jose R. ConeJo-García, “Methyltransferase inhibitors restore SATB1 protective activity against cutaneous T cell lymphoma in mice”, J Clin Invest. 2020. https://www.jci.org/articles/view/135711 https://doi.org/10.1172/JCI135711.

Provided by Moffitt Cancer Center and Research Institute

Brain Stem Cells Divide Over Months (Neuroscience)

For the first time, scientists at the University of Zurich have been able to observe stem cells in the adult mouse brain that divide over the course of several months to create new nerve cells. The study shows that brain stem cells are active over a long period, and thus provides new insights for stem cell research.

The picture shows the development over time from the stem cell (in red) via its daughter cells (orange and yellow depending on their stage of development) into new nerve cells (green) that have formed in the adult hippocampus over the course of several months. © UZH

Stem cells create new nerve cells in the brain over the entire life span. One of the places this happens is the hippocampus, a region of the brain that plays a significant role in many learning processes. A reduction in the number of newly formed nerve cells has been observed, for example, in the context of depression and Alzheimer’s disease, and is associated with reduced memory performance in these conditions.

From stem cell behavior to the activity of genes in individual cells

In a study published in Nature Neuroscience, the group around Sebastian Jessberger, a professor at the University of Zurich’s Brain Research Institute, has shown that stem cells in the hippocampus of mice are active over a period of several months. The researchers, led by PhD candidate Sara Bottes and postdocs Baptiste Jaeger and Gregor Pilz, employed state-of-the-art microscopy and genetic analyses (using single-cell RNA sequencing) of stem cells and their daughter cells to analyze the formation of new nerve cells. This enabled them to observe that specific stem cell populations are active over months and can divide repeatedly. This had already been suspected in earlier studies, but this is the first time there has been direct evidence. The researchers have also been able to use single-cell RNA sequencing of stem cells and their daughter cells to demonstrate that stem cells with different division behavior (few cell divisions as opposed to long-lasting stem cell activity) can be differentiated on the basis of their molecular composition and expression of genes.

Harnessing stem cells for therapeutic purposes

“Combining two modern methods – two-photon microscopy and single-cell RNA sequencing – has enabled us to identify precisely the stem cells that can divide over the course of months,” explains Jessberger. He adds that the evidence they have now presented of long-lasting stem cell division has implications for future therapeutic approaches: “We now know that there really are stem cells that divide over a period of many months. Single-cell RNA sequencing gives us our first insight into what genes are important in terms of the division behavior of individual cells.”

The new findings will form the basis of future endeavors to investigate in detail how specific genes control the activity of stem cells. Jessberger sums up the next research objectives: “Imaging and single-cell RNA sequencing have given us completely new insights that we’ll now use to be able to systematically regulate the activity of certain genes in the future. Since we now know that there are stem cells that can divide over a longer period, going forward we want to try to increase the division activity of these cells and thus the formation of new nerve cells, for example in the context of neurodegenerative conditions such as Alzheimer’s disease.”

Other scientists involved were John Cole, Merit Kruse, Vladislav Korobeynyk, Izaskun Mallona, and Fritjof Helmchen at UZH, Lachlan Harris and François Guillemot at the Francis Crick Institute (UK), and David Jörg and Benjamin Simons of the University of Cambridge (UK).

Reference: Bottes S, Jaeger BN, Pilz GA, Jörg DJ, Cole JD, Kruse M, Harris L, Korobeynyk VI, Mallona I, Guillemot F, Helmchen F, Simons BD, Jessberger S. Long-term self-renewing stem cells in the adult mouse hippocampus identified by intravital imaging. Nature Neuroscience doi: 10.1038/s41593-020-00759-4

Provided by University of Zurich

Researchers Identify A Rare Genetic Bone Disorder Through Massive Sequencing Methods (Medicine)

They have used precision medicine to uncover and treat new skeletal disorders.

Researchers of the “Cell Biology and Physiology-LABRET” group of the University of Malaga (UMA), together with the Networking Biomedical Research Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), have described a new genetic skeletal disorder based on a precision medicine strategy.

Alteration of focal points revealing cell signaling problems in patients with skeletal dysplasia caused by mutations in LAMA5. Green represents immunofluorescence localization of Vinculin (focal adhesions), purple is Phalloidin (actin cytoskeleton) and blue represents nuclei. © University of Malaga

By using methods of massive sequencing -of all genes- they have identified the mutations that caused a rare bone disorder, particularly, the mutations in “LAMA5”, the gene encoding an extracellular matrix protein around blood vessels in skeletal tissue.

This disorder consists in an extreme bone fragility combined with a lack of mineralization and skeletal deformity associated with joint dislocation and heart diseases, as well as a pulmonary insufficiency that causes perinatal mortality -at the time of birth.

The study was carried out at the Andalusian Centre for Nanomedicine and Biotechnology (BIONAND), in collaboration with the International Skeletal Dysplasia Registry of the University of California (Los Angeles), where the sequencing of affected patients’ genes was conducted. The Masaryk University (Czech Republic) also participated in the study.

“Our scientific team has been researching rare genetic syndromes affecting the skeleton for years, with a view to find a medical solution for patients with complicated diagnosis and treatment”, explains the researcher of the Department of Cell Biology, Iván Durán, main author of the study, which findings have been published in the scientific journal EBIOMEDICiNE.

According to this expert, precision medicine is the key to uncovering the genetic and molecular factors that produce this type of pathologies, and hence understanding the mechanism that causes them, enabling the development of tailored therapies.

Therefore, the researchers of the UMA have also described the mechanism of disease by generating cell models based on gene editing, simulating the mutations in LAMA5 in order to confirm if these mutations are the cause and determine the molecular process that triggers the problem. These cell models were developed by gene editing with CRISPR, introducing mutations causing a null or hypomorphic gene.

New mechanism of disease

“Thanks to these models we uncovered a new signaling pathway governing the skeleton formation -that makes the bone grow and stay healthy-, which means that our work has not only revealed a new disease, but also an unknown mechanism that could be used for common bone conditions”, says Durán.

As he clarifies, the presence of LAMA5 among cells involved in the skeleton formation indicates, therefore, that the appearance of signals from special blood vessels could be a highly effective means of bone repair and regeneration.

“Not only do blood vessels provide irrigation to bones, but also convey signals and support niches for stem cells that can be mobilized to induce a regenerative process. It seems that LAMA5 is a key component to support pericyte-like stem cells”, he clarifies.

New osteogenic biomaterial

Osteoporosis and osteogenesis imperfecta are diseases that cause bone fragility and affect a significant percentage of the population. Besides, these pathologies often present bone defects that are very difficult to repair. These scientific breakthrough will facilitate the design of new treatments and strategies for all types of bone fragility conditions.

In this sense, the “Cell Biology and Physiology” group of the UMA, which also belongs to the Biomedical Research Institute of Malaga (IBIMA), along with CIBER-BBN and the Cell Therapy Network, progress on a new project to develop an osteogenic biomaterial that would heal complex fractures in individuals with bone fragility and a low capacity of bone regeneration.

Reference: Barad M, Csukasi F, Kunova-Bosakova M, Martin J, Zhang W, Taylor SP, Dix P, Lachman R, Zieba J, Bamshad M, Nickerson D, Chong JX, Cohn DH, Krejci P, Krakow D, Duran I. Mutations in LAMA5 disrupts a skeletal noncanonical focal adhesion pathway and produces a distinct bent bone dysplasia. 2020 EBioMedicine. Nov 23;62:103075. doi: 10.1016/j.ebiom.2020.103075

Provided by University of Malaga