A ‘Tasty’ Protein May Lead to New Ways to Treat Metabolic and Immune Diseases (Biology)

The same taste-sensing molecule that helps you enjoy a meal from your favorite restaurant may one day lead to improved ways to treat diabetes and other metabolic and immune diseases.

TRPM5 is a specialized protein that is concentrated in the taste buds, where it helps relay messages to and from cells. It has long been of interest to researchers due to its roles in taste perception and blood sugar regulation.

Now, a team led by scientists at Van Andel Institute has published the first-ever high-resolution images of TRPM5, which reveal two areas that may serve as targets for new medications. The structures also may aid in the development of low-calorie alternative sweeteners that mimic sugar. The findings were published today in Nature Structural and Molecular Biology.

Wei Lü, Ph.D.
Wei Lü, Ph.D.

“TRPM5 is the cornerstone of taste signaling, which itself has a much larger role in the body than often recognized,” said Wei Lü, Ph.D., an associate professor at VAI and co-corresponding author of the study. “We hope our structures of TRPM5 will serve as blueprints for designing new medications that help control blood sugar in diabetes, while also providing a template for development of low-calorie sweeteners that activate sensory circuits in the brain and the gut — a key distinction that mimics sugar.”

There are five types of taste that the body senses: sweet, sour, salty, bitter and umami. When the tongue encounters a taste, specialized cells on the tongue called taste receptors send messages about that taste to the brain. TRPM5 is a key part of the complex process that ushers these important signals on their way to the brain’s sensory processing center.

Juan Du, Ph.D.
Juan Du, Ph.D.

But taste perception goes far beyond helping us sense the subtle flavors of a tiramisu. It helps protect the body by detecting bitter and acidic tastes, which commonly are associated with harmful substances. Taste perception also occurs beyond the tongue; for example, the process of taste perception in certain pancreatic cells regulates insulin secretion, which keeps blood sugar levels in check. Similar cells, called tuft cells, also coat the linings of the intestine, lungs and gallbladder, where they use TRPM5 and related proteins to sense the sugar-like byproducts of parasitic infections and trigger immune responses to deal with the threat.

“Targeting TRPM5 and taste-signaling throughout the body has two major potential benefits: it may help us improve treatment for a number of metabolic and immune disorders while also providing a path toward improved sweeteners,” said Juan Du, Ph.D., an associate professor at VAI and co-corresponding author of the study. “While the body needs sugar to survive, too much of it can be harmful. We’re hopeful a more thorough understanding of TRPM5 will lead to better alternatives.”

TQTRPM5 belongs to the TRP superfamily, a group of proteins that mediate responses to sensory stimuli, such as pain, pressure, vision, temperature and taste. Broadly known as ion channels, proteins like TRP nestle within cells’ membranes, acting as gatekeepers for chemical signals passing into and out of the cell. The eight proteins that comprise the TRPM subfamily are part of this broader group.

To date, Lü and Du laboratories have solved the structures of three of the eight known TRPM proteins as well as an ion channel called CALHM2, which belongs to the calcium homeostasis modulator family. Another member of this molecular family is CALHM1, also an important component of taste signaling.

Postdoctoral fellow Zheng Ruan, Ph.D., Van Andel Institute Graduate School Ph.D. candidate Emery Haley and Senior Research Scientist Ian J. Orozco, Ph.D., are co-first authors of the study. Other authors include Mark Sabat, Ph.D., and Richard Myers, Ph.D., of Takeda California, Inc., and Rebecca Roth of VAI. The structures were resolved in collaboration with the David Van Andel Advanced Cryo-Electron Suite at VAI.

Research reported in this publication was supported by Van Andel Institute; the National Heart, Lung, and Blood Institute of the National Institutes of Health under award no. R56HL144929 (Lü) and R01HL153219 (Lü); a McKnight Scholar Award (Du); a Klingenstein-Simons Scholar Award (Du); a Sloan Research Fellowship in neuroscience (Du); and a Pew Scholars in Biomedical Research Award from the Pew Charitable Trusts (Du). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or other granting organizations.

Lü also is supported by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health under award no. R01NS112363 and by the National Institute of General Medical Sciences of the National Institutes of Health under award no. R35GM138321. Du also is supported by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health under grant no. R01NS111031. Ruan is supported by an American Heart Association postdoctoral fellowship under award no. 20POST35120556.


Reference: Ruan, Z., Haley, E., Orozco, I.J. et al. Structures of the TRPM5 channel elucidate mechanisms of activation and inhibition. Nat Struct Mol Biol (2021). https://doi.org/10.1038/s41594-021-00607-4


Provided by Van Andel Institute

New Findings On Body Axis Formation (Biology)

Heidelberg researchers discover an enzyme that prevents the formation of multiple heads and axes in the freshwater polyp Hydra

In the animal kingdom, specific growth factors control body axis development. These signalling molecules are produced by a small group of cells at one end of the embryo to be distributed in a graded fashion toward the opposite pole. Through this process, discrete spatial patterns arise that determine the correct formation of the head-foot axis. A research team at the Centre for Organismal Studies (COS) at Heidelberg University recently discovered an enzyme in the freshwater polyp Hydra that critically shapes this process by limiting the activity of certain growth factors.

In particular, the proteins of the so-called Wnt signalling pathway play an important role in the pattern formation of the primary body axis. Wnt proteins, which arose early during evolution, are considered to be universal developmental factors. “Misregulation of Wnt factors can cause serious malformations during embryonic development and give rise to diseases such as cancer,” explains Prof. Dr Özbek, a member of the “Molecular Evolution and Genomics” department led by Prof. Dr Thomas Holstein at the COS.

Now, the researchers have discovered an enzyme in the freshwater polyp Hydra that can break down Wnt proteins, thereby deactivating them. Hydra is a basal multicellular organism of the phylum Cnidaria that has long been used as a model organism to study the Spemann-Mangold organizer, an embryonic signalling centre in charge of forming the body’s longitudinal axis. The Wnt proteins responsible for this process are continually produced in the mouth region of the adult polyp to maintain the body axis.

The researchers determined that the newly discovered HAS-7 enzyme develops in a ring-shaped zone below Hydra’s tentacle wreath. This region separates the head from the body. If HAS-7 production is experimentally interrupted by suppressing the gene expression, a fully formed second head and a second body axis spontaneously develop. According to Prof. Özbek, something similar occurs when Wnt proteins are artificially produced in the animal’s entire body.

In cooperation with Prof. Dr Walter Stöcker’s group at Mainz University, the Heidelberg researchers were able to show that the HAS-7 enzyme is capable of specifically cleaving the Wnt protein to suppress its activity beyond the head. Without this inhibitory mechanism, the Wnt emanating from the head floods the body, creating a two-headed animal. The HAS-7 enzyme is a member of the astacin family of proteases, which were first identified in crayfish. “Members of the astacin protease family are also found in higher vertebrates. It is therefore likely that we have found a mechanism here that may play a role in humans as well,” states Prof. Holstein.

In a follow-up project within the Collaborative Research Centre 1324 “Mechanisms and Functions of Wnt Signaling”, the researchers will collaborate with Prof. Dr Irmgard Sinning of the Heidelberg University Biochemistry Center to study the molecular mechanism of Wnt cleavage by astacin. “We hope to be able to find clues on the precise point of attack in the Wnt protein,” states Prof. Özbek.

In addition to the Heidelberg researchers from the COS and the Institute for Applied Mathematics, scientists from the German Cancer Research Center, Mainz University, the University of Innsbruck (Austria), the Leiden University Medical Center (Netherlands), and the University of Manitoba (Canada) also contributed to the study. Funding was provided by the German Research Foundation and the Canadian Institutes of Health Research, among others. The results of the research were published in the journal “BMC Biology”.

Featured image: The illustration depicts a two-headed Hydra in which the HAS-7 activity was experimentally blocked. | © Berenice Ziegler (COS)


ORIGINAL PUBLICATION

B. Ziegler, I. Yiallouros, B. Trageser, S. Kumar, M. Mercker, S. Kling, M. Fath, U. Warnken, M. Schnölzer, T. W. Holstein, M. Hartl, A. Marciniak-Czochra, J. Stetefeld, W. Stöcker, S. Özbek: The Wnt-specific astacin proteinase HAS-7 restricts head organizer formation in Hydra. BMC Biology (9 June 2021)


Provided by University of Heidelberg

Automated Microarray Rapid Test For Detecting SARS-CoV-2 Antibodies (Medicine)

During the continued progression of the Corona pandemic, rapid, inexpensive, and reliable tests will become increasingly important to determine whether people have the associated antibodies – either through infection or vaccination. Researchers at the Technical University of Munich (TUM) have now developed such a rapid antibody test. It provides the result in only eight minutes; the aim is to further reduce the process time to four minutes.

There are currently more than 20 different test procedures available for determining whether a person has antibodies against the new Corona virus. The waiting times for the results range between ten minutes and two and a half hours.

Matrix effects reduce the sensitivity of many of the methods. The more sensitive assays require numerous steps, making them expensive. In addition, most tests can identify only a single kind of antibody, forcing a choice between testing either for immunity through vaccination or through survived infection.

An interdisciplinary research team at the Technical University of Munich, led by the Chair of Analytical Chemistry and Water Chemistry, has now developed a low-cost automated rapid test that is highly sensitive and highly specific in detecting the three most important antibodies. The project, called CoVRapid, was funded by the Bavarian Research Foundation (BFS).

Modification of a proven process

The measurement is carried out on a foil-based sensor chip using the MCR microarray analysis platform of the Munich-based supplier GWK Präzisionstechnik GmbH. The device displays its measurement results within a few minutes after injecting a blood sample.

Today, the procedure still takes eight minutes, but building on current research, the waiting time will soon be reduced to just four minutes. IgG antibodies against a protein fragment of the SARS-CoV-2 receptor binding domain (RBD), the spike protein (S1 fragment) and the nucleocapsid protein (N) are simultaneously analyzed.

Deployable against new mutants

New mutant proteins can be very easily integrated into the chip. For this project, the research team is collaborating with the Planegg-based company ISAR Bioscience, which produces the respective viral proteins biotechnologically and modifies them for analytical use. The process used to fix the proteins onto the sensor chip has been tried and tested for many years.

“We have already developed reliable rapid tests for antibiotics in milk and for Legionella using this technology platform,” says adjunct teaching professor Dr. Michael Seidel, head of the Bioanalytics and Microanalytical Systems group at TUM’s Department of Analytical Chemistry and Water Chemistry. “The system has already proven itself in practical use. Our ‘CoVRapid’ rapid test may thus be deployed in clinics, medical offices and research laboratories in the very near future.”

The new test will answer questions about corona immunity

However, the new rapid test can do even more: the microarray technology, which allows to accommodate up to 100 measurement points on a single chip, is so sensitive that it can even determine the concentration of antibodies in a sample.

“The present research begs questions like: How well do vaccinations work? How long does immunity last? When will vaccinations need to be readministered? With its high sensitivity, our CoVRapid will help us find the answers to these questions,” says lead author Julia Klüpfel.

In the long term, the team is also planning on including other pathogens in the panel so the assay can be used, for example, to evaluate the effectiveness of an influenza vaccination.

Publications:

Klüpfel, J.; Koros, R.; Dehne, K.; Ungerer, M.; Würstle, S.; Mautner, J.; Feuerherd, M.; Protzer, U.; Hayden, O.; Elsner, M.; Seidel, M.
Automated, flow-based chemiluminescence microarray immunoassay for the rapid multiplex detection of IgG antibodies to SARS-CoV-2 in human serum and plasma (CoVRapid CL-MIA)
Analytical and Bioanalytical Chemistry, 13.05.2021 – DOI: 10.1007/s00216-021-03320-9

More information:

In addition to the Chair of Analytical Chemistry and Water Chemistry (Prof. Elsner) and the associated Bioanalytics and Microanalytical Systems Group (PD Dr. Seidel), the Institute of Molecular Immunology and Experimental Oncology (Prof. Knolle), the Institute of Virology (Prof. Protzer) and the Heinz Nixdorf Chair of Biomedical Electronics (Prof. Hayden) were involved in the project.

The CoVRapid project is funded by the Bavarian Research Foundation (AZ-1438-20C). The microarray analysis platform MCR 3 and its successor generation, MCR-R were made available by the Munich-based company GWK Präzisionstechnik GmbH. Recombinant antigens were produced by ISAR Bioscience. Safety-relevant steps were performed in the biosafety laboratory of the Central Institute for Translational Cancer Research (TranslaTUM).

Featured image: Lead author Julia Klüpfel with a measuring chip at the laboratory of the Central Institute for Translational Cancer Research (TranslaTUM). © Sebastian Kissel / TUM


Provided by TUM

A New Type of Homo Unknown to Science (Paleontology)

  • The discovery of a new Homo group in this region, which resembles Pre-Neanderthal populations in Europe, challenges the prevailing hypothesis that Neanderthals originated from Europe, suggesting that at least some of the Neanderthals’ ancestors actually came from the Levant.
  • The new finding suggests that two types of Homo groups lived side by side in the Levant for more than 100,000 years (200-100,000 years ago), sharing knowledge and tool technologies: the Nesher Ramla people who lived in the region from around 400,000 years ago, and the Homo sapiens who arrived later, some 200,000 years ago.
  • The new discovery also gives clues about a mystery in human evolution: How did genes of Homo sapiens penetrate the Neanderthal population that had presumably lived in Europe long before the arrival of Homo sapiens?
  • The researchers claim that at least some of the later Homo fossils found previously in Israel, like those unearthed in the Skhul and Qafzeh caves, do not belong to archaic (early) Homo sapiens, but rather to groups of mixed Homo sapiens and Nesher Ramla lineage.

Nesher Ramla Homo type – a prehistoric human previously unknown to science: Researchers from Tel Aviv University and the Hebrew University of Jerusalem have identified a new type of early human at the Nesher Ramla site, dated to 140,000 to 120,000 years ago. According to the researchers, the morphology of the Nesher Ramla humans shares features with both Neanderthals (especially the teeth and jaws) and archaic Homo (specifically the skull). At the same time, this type of Homo is very unlike modern humans – displaying a completely different skull structure, no chin, and very large teeth. Following the study’s findings, researchers believe that the Nesher Ramla Homo type is the ‘source’ population from which most humans of the Middle Pleistocene developed. In addition, they suggest that this group is the so-called ‘missing’ population that mated with Homo sapiens who arrived in the region around 200,000 years ago – about whom we know from a recent study on fossils found in the Misliya cave.

Two teams of researchers took part in the dramatic discovery, published in the prestigious Science journal: an anthropology team from Tel Aviv University headed by Prof. Israel Hershkovitz, Dr. Hila May and Dr. Rachel Sarig from the Sackler Faculty of Medicine and the Dan David Center for Human Evolution and Biohistory Research and the Shmunis Family Anthropology Institute, situated in the Steinhardt Museum at Tel Aviv University; and an archaeological team headed by Dr. Yossi Zaidner from the Institute of Archaeology at the Hebrew University of Jerusalem.

Timeline: The Nesher Ramla Homo type was an ancestor of both the Neanderthals in Europe and the archaic Homo populations of Asia.

Fossil remains of skull and jaw. © Tel Aviv University

Prof.Israel Hershkovitz: “The discovery of a new type of Homo” is of great scientific importance. It enables us to make new sense of previously found human fossils, add another piece to the puzzle of human evolution, and understand the migrations of humans in the old world. Even though they lived so long ago, in the late middle Pleistocene (474,000-130,000 years ago), the Nesher Ramla people can tell us a fascinating tale, revealing a great deal about their descendants’ evolution and way of life.”

The important human fossil was found by Dr. Zaidner of the Hebrew University during salvage excavations at the Nesher Ramla prehistoric site, in the mining area of the Nesher cement plant (owned by Len Blavatnik) near the city of Ramla. Digging down about 8 meters, the excavators found large quantities of animal bones, including horses, fallow deer and aurochs, as well as stone tools and human bones. An international team led by the researchers from Tel Aviv and Jerusalem identified the morphology of the bones as belonging to a new type of Homo, previously unknown to science. This is the first type of Homo to be defined in Israel, and according to common practice, it was named after the site where it was discovered – the Nesher Ramla Homo type.

Dr. Yossi Zaidner: “This is an extraordinary discovery. We had never imagined that alongside Homo sapiens, archaic Homo roamed the area so late in human history. The archaeological finds associated with human fossils show that “Nesher Ramla Homo” possessed advanced stone-tool production technologies and most likely interacted with the local Homo sapiens“. The culture, way of life, and behavior of the Nesher Ramla Homo are discussed in a companion paper also published in Science journal today.

Prof. Hershkovitz adds that the discovery of the Nesher Ramla Homo type challenges the prevailing hypothesis that the Neanderthals originated in Europe. “Before these new findings,” he says, “most researchers believed the Neanderthals to be a ‘European story’, in which small groups of Neanderthals were forced to migrate southwards to escape the spreading glaciers, with some arriving in the Land of Israel about 70,000 years ago. The Nesher Ramla fossils make us question this theory, suggesting that the ancestors of European Neanderthals lived in the Levant as early as 400,000 years ago, repeatedly migrating westward to Europe and eastward to Asia. In fact, our findings imply that the famous Neanderthals of Western Europe are only the remnants of a much larger population that lived here in the Levant – and not the other way around.”

According to Dr. Hila May, despite the absence of DNA in these fossils, the findings from Nesher Ramla offer a solution to a great mystery in the evolution of Homo: How did genes of Homo sapiens penetrate the Neanderthal population that presumably lived in Europe long before the arrival of Homo sapiens? Geneticists who studied the DNA of European Neanderthals have previously suggested the existence of a Neanderthal-like population which they called the ‘missing population’ or the ‘X population’ that had mated with Homo sapiens more than 200,000 years ago. In the anthropological paper now published in Science, the researchers suggest that the Nesher Ramla Homo type might represent this population, heretofore missing from the record of human fossils. Moreover, the researchers propose that the humans from Nesher Ramla are not the only ones of their kind discovered in the region, and that some human fossils found previously in Israel, which have baffled anthropologists for years – like the fossils from the Tabun cave (160,000 years ago), Zuttiyeh cave (250,000), and Qesem cave (400,000) – belong to the same new human group now called the Nesher Ramla Homo type.

“People think in paradigms,” says Dr. Rachel Sarig. “That’s why efforts have been made to ascribe these fossils to known human groups like Homo sapiens, Homo erectus, Homo heidelbergensis or the Neanderthals. But now we say: No. This is a group in itself, with distinct features and characteristics. At a later stage small groups of the Nesher Ramla Homo type migrated to Europe – where they evolved into the ‘classic’ Neanderthals that we are familiar with, and also to Asia, where they became archaic populations with Neanderthal-like features. As a crossroads between Africa, Europe and Asia, the Land of Israel served as a melting pot where different human populations mixed with one another, to later spread throughout the Old World. The discovery from the Nesher Ramla site writes a new and fascinating chapter in the story of humankind.”

Prof. Gerhard Weber, an associate from Vienna University, argues that the story of Neanderthal evolution will be told differently after this discovery: “Europe was not the exclusive refugium of Neanderthals from where they occasionally diffused into West Asia. We think that there was much more lateral exchange in Eurasia, and that the Levant is geographically a crucial starting point, or at a least bridgehead, for this process.”

Link to the research video:

https://www.youtube.com/watch?v=OGPKRuyd-5M

Link to the research video:

https://www.youtube.com/watch?v=OGPKRuyd-5M

The study, “A Middle Pleistocene Homo from Nesher Ramla, Israel”, Science, 2021. DOI: https://doi.org/10.1126/science.abh3169

Featured image: Static skull & mandible & parietal orthographic © Tel Aviv University


Provided by Tel Aviv University

How Motor Cortex Influences Stress Responses in Brain Regions Involved in Drug- and Alcohol-seeking Behavior? (Neuroscience)

Novel discovery describes how the motor cortex influences stress responses in brain regions involved in drug- and alcohol-seeking behavior

THE IDEA

This may lead to collaboration to look for targets affecting the motor cortex and to think about activity in a new light. The research suggests that movement and exercise could become a prescription.

Building on recent work, researchers including Danny Winder, director of the Vanderbilt Center for Addiction Research have developed a clear picture of how particular circuitry in the brain may be involved in drug- and alcohol-seeking behavior. They derived a control network for the bed nucleus of the stria terminalis, a part of a larger brain region sometimes called the extended amygdala.

The researchers used light sheet microscopy, a technique that enables rapid and three-dimensional imaging of the entire brain, to review every part of the brain that connects to the BNST circuit. These studies were done in parallel with studies exploring the activity of this circuit. By exploring the activity of this circuit in association with a brief stressor (restraint), rather than lengthy alcohol abstinence assays, they were able to accomplish in two and a half days what would have otherwise taken 15 years.

Through this analysis the researchers could trace the relationship of inputs and outputs to confirm how the circuit works. Surprisingly, the study revealed the top regions of the brain that control the BNST network are the motor and premotor cortices, which are involved in execution and planning of movement.

WHY IT MATTERS

The motor cortex in the brain plays a major role in virtually every move we make and affects other aspects of our lives in unexpected ways. For example, we can’t tickle ourselves because this part of our brain tells us that skin is about to be touched, we have a smooth visual field because the motor cortex tells the occipital cortex that our eyes are moving and anticipates where we’re going to look next. Movement is the most important and basic principle of animal biology, and systems must work together to make that happen, Winder said.

Danny Winder © Vanderbilt University

“We are beginning to see now how the motor cortex inputs impact brain circuits involved in potential relapse to drug- and alcohol-seeking behavior,” said Winder, also Bixler-Johnson-Mayes Professor of Molecular Physiology and Biophysics, Pharmacology, and Psychiatry. “We suspect there are multiple ways that this process can be regulated, both positive and negative. Whereas exercise might have positive impact on sobriety, other motor activity may coordinate with inputs to this region of the brain that have an adverse effect.”

The research also emphasizes the impact that advanced neuroscience tools are having on the field over the past decade. The light sheet microscope allowed us to stop looking “under the lamppost,” Winder said. “By using a higher throughput unbiased approach, we have opened a new area of neurobiology—the connection of motor cortex with affective circuitry.”

WHAT’S NEXT

Winder expects to dive into this work to understand and describe how this affective circuitry works to describe phenomena like “runner’s high.”

Ultimately, this early work may lead to collaboration with genomics and proteomics experts to look for novel targets on the input affecting the motor cortex, to think about activity in a new light. The research suggests that movement and exercise could become a prescription.

FUNDING

This research supported by the National Institute on Alcohol Abuse and AlcoholismNational Institute on Drug AbuseNational Institute of Diabetes and Digestive and Kidney Diseases and National Institute of General Medical Sciences of the National Institutes of Health. Additional funding was provided by the Brain and Behavior Research Foundation.

GO DEEPER

The article, Delineation of an insula-BNST circuit engaged by struggling behavior that regulates avoidance in mice, was published in the journal Nature Communications on June 11.

The collaboration within VCAR, itself a trans-institutional program included work from labs specializing in behavior and physiology, neuroanatomy and molecular physiology and biophysics. The stitching between the labs was made possible through the efforts of trainees Joe Luchsinger and Samuel Centanni.

Other co-authors and contributors to the study are Jose Maldonado and Richard B. Simerly, research instructor and professor of molecular physiology and biophysics, respectively and Winder lab trainees Tracy FetterlyGreg SalimandoMarie DoyleKellie M. Williford, NSO outreach coordinator for the Vanderbilt Brain Research also participated in the work.

Featured image: Series of de-lipidated (“cleared”) mouse brains imaged using light sheet microscopy to reveal neural circuits marked by viral tracing strategies. © Vanderbilt University


Provided by Vanderbilt University

Astrophysicists Prepare for Age of Multimessenger Astronomy; Build Galaxy Catalog to Study Black Holes (Astronomy)

THE IDEA

Led by postdoctoral fellow researcher Maria Charisi, a team of international researchers known as the NANOGrav collaboration has created a catalog of 45,000 galaxies to detect gravitational waves created by pairs of black holes known as binaries. Using pulsars—the most precise clocks of the sky—a galactic scale detector dubbed a pulsar timing array and infrared data from across the sky, Charisi used the catalog to input hypothetical binaries to measure differences in the masses of the two black holes or their distance from each other within a galaxy. “Since we haven’t found gravitational waves with pulsar timing arrays yet, we can play with our binary parameters and a range of gravitational wave frequencies to find the limits of the sizes of black hole binaries in specific galaxies,” Charisi said.

From this work, astrophysicists can rule out the existence of certain types of binaries in several nearby galaxies. Within our own galaxy, scientists know a central supermassive black hole exists, but not if there is a smaller companion forming a binary. Although pulsar timing arrays cannot constrain a binary in our Milky Way, the experiment is so sensitive that these limits are similar to limits in our own galaxy obtained with other methods.

WHY IT MATTERS

This is the first time that pulsar timing array data has been explored with the accompanying galaxy catalog. By calculating the limits of black hole binaries in nearby galaxies, Charisi, Stephen Taylor, assistant professor of physics and astronomy, and their international colleagues are preparing for an age of multimessenger astronomy. As black hole binaries interact together and within their galactic environment consisting of gas and stars, scientists will be able to interpret multimessenger signals full of rich information about the composition and behavior of galaxies. “We have never seen a black hole binary before, so we know very little at present,” Taylor said. “There is much theoretical debate about how a binary evolves, and seeing one will be the Rosetta stone of our field. We are preparing for this moment.”

WHAT’S NEXT

As experiment becomes more sensitive with more observations, Charisi and Taylor expect to probe more galaxies, looking at scenarios from even larger samples. Ultimately with this data and upon the first detection of gravitational waves, scientists will be able to pinpoint the galaxy from which the signals came.

FUNDING

The NANOGrav project receives support from National Science Foundation Physics Frontiers Center award number 1430284. Charisi and Taylor received support from NSF award 2007993.

GO DEEPER

The article, “The NANOGrav 11 yr Data Set: Limits on Supermassive Black Hole Binaries in Galaxies within 500 Mpc”  was published in Astrophysical Journal on June 22.


Provided by Vanderbilt University

Uncovered: Crucial Insight Into How Ebola Virus Evades Our Immune Defenses (Medicine)

Monash University, Australia, researchers have discovered a key way that one of the world’s deadliest pathogens, Ebola virus, evades the immune system

Understanding this process provides new potential targets for the future development of anti-viral therapies for a disease that killed over 11,000 people in an outbreak in West Africa between 2014 and 2016, with mortality rates in past outbreaks of 25 per cent to 90 per cent.

An outbreak of Ebola, for which treatment options are extremely limited, occurred earlier this year in the Democratic Republic of Congo. In common with viruses such as the Hendra and rabies viruses, Ebola infects humans from animals, with bats thought to be the natural hosts.

The research team, led by Dr Greg Moseley and Dr Angela Harrison from the Monash University Biomedicine Discovery Institute, in collaboration with researchers at the Australian Centre for Disease Preparedness (ACDP, CSIRO) found that Ebola virus can block the function of the STAT3 protein, a critical messenger” protein that transmits signals within our cells important to regulating host immune and inflammatory responses against infections.

Importantly, using infections with pathogenic virus under the highest biocontainment level (BSL4) together with gene expression analysis and quantitative single cell imaging, the research team have discovered that STAT3 activity is antiviral toward Ebola virus, but that Ebola virus uses a protein called VP24 to target and disable STAT3’s messenger function through at least two different strategies, including binding to STAT3 protein complexes.

The findings were published today in the journal PLOS Pathogens.

The elucidation of this entirely new way for Ebola virus to disarm immune responses may provide new targets that can be used in research towards developing new anti-virals that prevent Ebola virus, and possibly other viruses, from interfering with the infected person’s antiviral system, allowing them to fight off the disease, according to Dr Moseley. “This shows us that Ebola virus uses more tricks to evade and dysregulate the immune system than we previously thought, and highlights the expanding importance of targeting of STAT3 by viruses. Understanding this process gives us new potential targets that might contribute to developing therapies that block the ability of Ebola and other viruses to shut down the immune response,” he said.

Importantly the STAT3 pathway is also involved in the pathogenesis of many other diseases, including cancers. Dr Moseley believes that understanding how Ebola virus and other viruses specifically target and modify STAT3 could also provide new directions for the development of therapeutics for diseases such as cancer.

Read the full paper in PLOS Pathogens titled: Antagonism of STAT3 signalling by Ebola virus


Provided by Monash University

Genetic Study of Liver Cancer Reveals New Drug Target (Biology)

Drugs targeting the gene MAGEA3 may help block the growth of hepatocellular carcinoma (HCC), the most common type of primary liver cancer and one of the leading causes of cancer deaths in the country. That’s one conclusion of a new study analyzing the genetics of HCC tumors published June 24th in the journal PLOS Genetics by Augusto Villanueva of the Icahn School of Medicine at Mount Sinai and colleagues.

Scientists have previously discovered several genes that drive the growth of HCC tumors, yet treatment benefit from approved drugs is still limited. In the new study, Villanueva and colleagues collected 44 tumor biopsies from 12 HCC patients. The researchers used RNA sequencing to study which genes were more highly expressed in high-grade regions of a tumor compared to low-grade regions of the same tumor.

One family of genes–cancer testis antigens (CTAs) -was recurrently over-expressed in the most aggressive regions of tumors. CTAs, most of which are located on the X chromosome, are usually expressed in male germ cells within the testes and are believed to play roles in spermatogenesis as well as protecting germ cells from stressors and cell death. Villanueva’s team found that CTAs, and especially MAGEA3, are associated with poor prognosis in HCCs. Moreover, when the group blocked the expression of MAGEA3 in isolated HCC cells, the cells could no longer proliferate and eventually died. When the group overexpressed MAGE3 in the liver cells of mice prone to HCC, the animals died of cancer more quickly. Future studies are needed to replicate the results in larger patient populations and probe whether MAGEA3 itself, or its downstream targets, are more effective to target therapeutically.

“The study uncovered the role of cancer testis antigens, specifically MAGEA3, in liver cancer progression,” Villanueva adds. “It demonstrates how selective inhibition of MAGEA3 has anti-tumoral effects on experimental models of this disease. Overall, the study provides the proof-of-principle to test MAGEA3 inhibition in early phase clinical trials for patient with primary liver cancer.”

Peer-reviewed; Experimental study; People

In your coverage please use this URL to provide access to the freely available article in PLOS Geneticshttp://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1009589

Funding: JvF was supported by the German Research Foundation (FE1746/1-1). IL was supported by a grant from the Swiss National Science Foundation (http://www.snf.ch/en/Pages/default.aspx), from Foundation Roberto & Gianna Gonella and Foundation SICPA (https://www.sicpa.com/sustainability/switzerland-institution-research-paraplegia). MRdG was supported by Fundación Alfonso Martín Escudero Fellowship (https://fundame.org/) and Damon Runyon-Rachleff Innovation Award (DR52-18). EB was supported by Damon Runyon-Rachleff Innovation Award (DR52-18). AL was supported by Damon Runyon-Rachleff Innovation Award (DR52-18), R37 Merit Award (R37CA230636), and DoD Translational Team Science Award (CA150272P2) and Icahn School of Medicine at Mount Sinai (https://icahn.mssm.edu/). The Tisch Cancer Institute and related research facilities are supported by P30 CA196521. AV is supported by the DoD Translational Team Science Award (CA150272P3). JML was supported by European Commission (EC)/Horizon 2020 Program (HEPCAR, Ref. 667273-2), EIT Health (CRISH2, Ref. 18053), Accelerator Award (CRUCK, AEEC, AIRC) (HUNTER, Ref. C9380/A26813), National Cancer Institute (P30-CA196521), U.S. Department of Defense (CA150272P3), Samuel Waxman Cancer Research Foundation (https://www.waxmancancer.org), Spanish National Health Institute (SAF2016-76390) and the Generalitat de Catalunya/AGAUR (SGR-1358). TGL is supported by the Spanish Association for the Study of the Liver (https://ww2.aeeh.es/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Featured image: Histological pictures of aggressive hepatic tumors obtained from transgenic mice (using tail vein injection of transposable genetic elements) with induced overexpression of MAGEA3. © Craig AJ et al., 2021, PLOS Genetics


Reference: Craig AJ, Garcia-Lezana T, Ruiz de Galarreta M, Villacorta-Martin C, Kozlova EG, Martins-Filho SN, et al. (2021) Transcriptomic characterization of cancer-testis antigens identifies MAGEA3 as a driver of tumor progression in hepatocellular carcinoma. PLoS Genet 17(6): e1009589. https://doi.org/10.1371/journal.pgen.1009589


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No Lab Required: New Technology Can Diagnose Infections in Minutes (Medicine)

Patients will be able to receive confirmed diagnosis at the doctor’s office

The idea of visiting the doctor’s office with symptoms of an illness and leaving with a scientifically confirmed diagnosis is much closer to reality because of new technology developed by researchers at McMaster University.

Engineering, biochemistry and medical researchers from across campus have combined their skills to create a hand-held rapid test for bacterial infections that can produce accurate, reliable results in less than an hour, eliminating the need to send samples to a lab.

Their proof-of-concept research, published today in the journal Nature Chemistry, specifically describes the test’s effectiveness in diagnosing urinary tract infections from real clinical samples. The researchers are adapting the test to detect other forms of bacteria and for the rapid diagnosis of viruses, including COVID-19. They also plan to test its viability for detecting markers of cancer.

“It’s going to mean that patients can get better treatment, faster results and avoid serious complications. It can also avoid the unnecessary use of antibiotics, which is something that can buy us time in the battle against antimicrobial resistance,” says Leyla Soleymani, the paper’s co-corresponding author and an associate professor of engineering physics.

“This will give doctors the science to support what they already suspect based on their skills and experience,” says co-corresponding author Yingfu Li, a professor of biochemistry and biomedical sciences.

The new DNA-based technology uses a handheld device similar to a blood-glucose monitor. A microchip analyzes a droplet of bodily fluid such as blood, urine or saliva, using molecules that can detect the specific protein signature of an infection. The device, about the size of a USB stick, plugs into a smartphone, which displays the result.

The invention combines electrochemical engineering technology developed by Soleymani and her team with biochemical technology developed by Li and his colleague Dingran Chang. They worked with infectious disease clinician Marek Smeija, a professor of medicine who provided samples from real patients, and with Todd Hoare, a professor of chemical engineering.

“As scientists, we want to enable things,” says Li, “We are knowledgeable in different scientific and engineering principles, and when you put them together to help people, that’s a special feeling. Having the chance to impact society is the reason we all do this work.”

Existing practice typically requires sending samples to laboratories to be cultured, a process that can take days. Providing immediate results to patients can reduce the spread of infection, improve patients’ quality of life and simplify the work of busy clinicians.

The new technology can distinguish strains of the same bacteria that can be treated with antibiotics from others that are resistant to antibiotics, a critical distinction that can help battle the growing problem of antimicrobial resistance, or AMR.

“Clinicians identified testing delays as a problem that needed to be resolved,” says Soleymani, who holds the Canada Research Chair in Miniaturized Biomedical Devices. “We wanted to build a system that could give as much information as possible to the physician during the patient’s first visit.”

The researchers are in the midst of testing an adaptation of the same technology for the virus that causes COVID-19, using samples from a Hamilton clinic.

“This technology is very versatile and we’re getting very close to using the same technology for COVID-19 testing,” says Li, who is also a member of McMaster’s Michael Groote Institute for Infectious Disease Research.

The researchers are exploring regulatory approvals and industry partnerships to get the technology into wide use as quickly as possible, not only in Canada, but around the world, especially where access to lab testing is limited or non-existent.

“I think this technology is a step toward democratizing disease diagnosis and management,” says lead author Richa Pandey, a post-doctoral research fellow in Soleymani’s lab. “This is technology that can go anywhere in the world where testing is needed.”

The research exemplifies the work of Canada’s Global Nexus for Pandemics and Biological Threats at McMaster University, which brings together an international network of researchers, government, industry, health care and other partners with the goal of finding solutions to the current pandemic, while preparing for future global health threats such as antimicrobial resistance.


Reference: Pandey, R., Chang, D., Smieja, M. et al. Integrating programmable DNAzymes with electrical readout for rapid and culture-free bacterial detection using a handheld platform. Nature Chemistry, 2021 DOI: 10.1038/s41557-021-00718-x


Provided by McMaster University