Daily Archives: 13 Nov 2020

Botany

The Popovich Of Floral Nectar Spurs (Botany)

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Scientists discover gene that directs spur development, name it after NBA Spurs coach.

When it came to naming a gene that could lead to new insights on a crucial feature of evolution, the Harvard Organismic and Evolutionary Biology alumna leading the project aimed for something rather tongue in cheek. She called it POPOVICH, after San Antonio Spurs coach and president Gregg Popovich.

Nectar spurs are the hollow tubes that bulge out from a number of flowers and are crucial to increasing biodiversity among flowering plants that have them. In many cases, species with nectar spurs are much more diverse than their close relative without this novel trait. ©Photos by Evangeline Ballerini

Evangeline Ballerini, Ph.D. ’10, an assistant professor of biological sciences at California State University, Sacramento, said she and her collaborators — including Harvard’s Elena Kramer — settled on the name because the newly discovered gene calls the shots for floral nectar spurs the way Popovich does for his NBA team.

“I ended up choosing to name it after Gregg Popovich, in part, because the gene plays a regulatory role in spur development, kind of like a coach controls the development of their team,” said Ballerini, who is a long-time Golden State Warriors fan and a part-time Celtics fan because of her time in the Boston area, but respects the Spurs and admires Popovich’s leadership.

The work is described in a recently published study in PNAS.

Nectar spurs are the hollow tubes that bulge out from a number of flowers and are crucial to increasing biodiversity among flowering plants that have them. In many cases, species with nectar spurs are much more diverse than their close relative without this novel trait.

In the paper, the scientists identify the gene critical to controlling the development of these spurs in the common columbine, or Aquilegia. They found it acts as a master regulator that appears to control the creation of the spurs by regulating the activity of other genes, the way a coach decides who plays and when.

Aside from the quirky NBA reference, what really has evolutionary biologists excited about the discovery is that the findings have the potential to help them understand how organisms get their vast array of shapes and traits, and then how those traits evolve.

Nectar spurs are considered a key innovation in flowers, meaning they are considered a novel feature — one that helps organisms make the greatest use of their environment and leads to a diversity boom. Animals that evolved to have wings, for instance, have spun off into number of different species over millions of years. Other key innovations are eyes or the backbone in mammals.

Most key innovations happened deep in the past, making identifying their origin increasingly difficult. In the group of plants the researchers studied, however, floral nectar spurs have only been around for about 5 to 7 million years.

“Given that the Aquilegia nectar spur evolved relatively recently and is formed by modifications to a single floral organ, it provides a unique opportunity to begin to dissect the developmental and genetic basis of a key innovation, which, in turn, will provide insight into its origin,” the researchers wrote.

The researchers believe the gene is among the first key innovations for which scientists have identified the critical gene, opening the door to a number of areas in understanding how form and morphology are achieved in flowers and other living things.

“We’re particularly interested in novel features that seem to be very important for promoting speciation events,” said Kramer, Bussey Professor of Organismic and Evolutionary Biology and chair of the Department of Organismic and Evolutionary Biology. “In terms of a morphological trait, like the nectar spur, we’re asking: How did development [of the species] change? … It gives us, essentially, a handle, a starting place to try to start understanding this genetic network.”

Researchers made the discovery using a combination of techniques that included genetic sequencing and crossing species, and gene expression analyses. One of the keys was using a species of the Aquilegia native to China and known to be the only member of that genus, out of 60 to 70 species, to lack nectar spurs.

The team started by repeating a 1960 study by the Russian geneticist W. Pra?mo that crossed the spurless flower with a spurred species and suggested that a single, recessive gene was responsible for spur loss. Unlike Pra?mo, they had the genetic tools to finish the job, and sequenced the genome of about 300 offspring. That narrowed the search to just over 1,000 genes. Further genetic sleuthing led them to POPOVICH, which they call POP for short, and confirmed it using a genetically modified virus that knocks down, or suppresses, targeted genes.

“We took a species that has spurs and normally has POP expression, and we downregulated the expression of POP,” Kramer said. “We showed that it lost its spurs, and that result was the thing that ties it all together. Not only is this a gene that’s specifically expressed in spurs, but when you knock it down, it loses its spurs.”

While this is all strong evidence, more work is needed to confirm their findings.

“There are several directions that we’d like to go in, including trying to figure out how POP expression is controlled, which genes POP regulates the expression of, and what the POP gene is doing in the spurless relatives of Aquilegia,” Ballerini said.

References : Evangeline S. Ballerini, Ya Min, Molly B. Edwards, Elena M. Kramer, Scott A. Hodges, “POPOVICH, encoding a C2H2 zinc-finger transcription factor, plays a central role in the development of a key innovation, floral nectar spurs, in Aquilegia”, Proceedings of the National Academy of Sciences Sep 2020, 117 (36) 22552-22560; link: https://www.pnas.org/content/117/36/22552 DOI: 10.1073/pnas.2006912117

Provided by Harvard University

Biology

Light Shed On The Atomic Resolution Structure Of Phage DNA Tube (Biology)

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Given that phages are able to destroy bacteria, they are of particular interest to science. Basic researchers from the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) in Berlin are especially interested in the tube used by phages to implant their DNA into bacteria. In collaboration with colleagues from Forschungszentrum Jülich and Jena University Hospital, they have now revealed the 3D structure of this crucial phage component in atomic resolution. The key to success was combining two methods – solid-state NMR and cryo-electron microscopy. The study has just been published in the journal Nature Communications.

Artistic representation of phages of the family Siphoviridae (yellow and blue) that infect a bacterial cell (green). The excerpt (circle) shows the atomic structure of the DNA tube (yellow), through which the phages inject their DNA into the bacterium. ©Visualization: Barth van Rossum, FMP

With growing antibiotic resistance, phages have increasingly become the focus of research. Phages are naturally occurring viruses with a very useful property: they implant their DNA into bacteria and proliferate there until the bacterial cell is ultimately destroyed. This is why they are also referred to as bacteriophages (bacteria eaters).

This approach has already been shown to fight multidrug-resistant bacteria. Last year, the case of a girl from England hit the headlines, when she was cured from a serious antibiotic-resistant infection using engineered phages.

However, the widespread use of phage therapy is still a long way off. Many of the underlying principles that are key to advancing this therapy are not yet understood. For example, little was previously known about the appearance of the exact architecture of the tube used by phages to implant their DNA into bacteria. Now scientists from the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) in Berlin, together with colleagues from Forschungszentrum Jülich and Jena University Hospital, have managed to reveal the 3D structure of this crucial phage component in atomic resolution.

Designed for transporting DNA

“The structure and flexibility of the DNA tube attached to the icosahedron-shaped capsid is somewhat reminiscent of a spinal column,” stated FMP’s Professor Adam Lange, describing one of the new findings. “It seems to be perfectly designed for transporting DNA.”

The researchers were able to gain fascinating insights into the structure and function of this sophisticated DNA transport pathway – in this case, from a variant of phage SPP1 – by innovatively combining solid-state NMR with cryo-electron microscopy (cryo-EM). Lange’s research group further developed nuclear magnetic resonance spectroscopy (NMR) especially for this task under an ERC Grant; cryo-EM expert Professor Gunnar Schröder from Forschungszentrum Jülich performed the electron-microscopic investigations. In addition, new modeling algorithms were required for the computer-based combination of the two data sets for structure determination. These algorithms were developed by Professor Michael Habeck from Jena University Hospital. “The key to success was combining the two methods, representing a methodological milestone,” commented Professor Lange.

While solid-state NMR is ideal for visualizing flexible structures and tiny details, cryo-EM provides insight into the overall architecture. The resulting image shows that six gp17.1 proteins organize into stacked rings, forming a hollow tube. The rings are connected by flexible linkers, making the tube very bendable. “We are now able to understand how negatively charged DNA is repelled from the likewise negatively charged interior wall of the flexible tube, passing through it smoothly,” explained FMP’s Maximilian Zinke, lead author of the study now published in Nature Communications. “The bacteria are ultimately destroyed via this pathway.”

Milestone for integrated structural biology

According to group leader Adam Lange, besides representing a quantum leap forward in phage research, the work will also advance “integrated structural biology”, the term for the combination of these two complementary methods.

Thanks to the recent installation of a new high-resolution Titan Krios electron microscope, the infrastructure required to achieve this is now available on Campus Berlin-Buch. Moreover, a 1.2 gigahertz device will soon be added to the existing NMR spectrometers. “Equipped with cryo-EM and the most sensitive NMR spectrometer in the world, we will be very present in integrative structural biology in the future,” enthused Adam Lange. “This offers bright prospects for the campus and for the research location of Berlin.”

References: Zinke, M., Sachowsky, K.A.A., Öster, C. et al. Architecture of the flexible tail tube of bacteriophage SPP1. Nat Commun 11, 5759 (2020). Link: https://www.nature.com/articles/s41467-020-19611-1 doi: https://doi.org/10.1038/s41467-020-19611-1

Provided by FV Berlin

Planetary Science

Preparing For A Human Mission To Mars (Planetary Science)

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Future human missions to Mars depend on field research in an environment similar to that of Mars. It will enable the evaluation of operational concepts and optimization of strategies. The goals and results of the AMADEE-18 Mars analog mission are detailed in a special collection of articles in the peer-reviewed journal Astrobiology. Click here to read the articles now.

Journal for the most up-to-date information and perspectives on exciting new research findings and discoveries emanating from interplanetary exploration and terrestrial field and laboratory research programs. ©Mary Ann Liebert, Inc., publishers

The AMADEE-18 expedition was designed in preparation for future human missions to the Mars surface. The mission took place in the Dhofar Desert in the Sultanate of Oman and was directed by a Mission Support Center in Austria. Brief descriptions of some of the papers in the collection follow.

A comprehensive overview of the mission, describing its technical and organizational infrastructure, is provided by Gernot Groemer, Austrian Space Forum, and coauthors. They describe the proposed workflow for coordinating the timing and location of the instruments and experiments. “In validation of this workflow, the decision-making interaction between the field and the Mission Support Center was studied,” state the authors.

A performance metrics analysis is presented by Sophie Gruber, Austrian Space Forum, and coauthors. Their aim is to develop a benchmarking tool for mission planning and evaluation. “We propose a method to compare analog missions across agencies, disciplines, and complexities/fidelities to improve scientific output and mission safety and maximize effectiveness and efficiency,” say the authors.

Methods to localize an unmanned aerial vehicle on Mars, such as an autonomous helicopter, were tested by Eren Allak, University of Klagenfurt, and coauthors. “In the absence of a global positioning system, a computationally efficient localization technology that can be applied on Mars is visual-inertial odometry (VIO). The AMADEE-18 mission provided an opportunity to test the feasibility of a state-of-the-art VIO algorithm and the camera in a Mars-like analog environment,” state the authors.

References: Gernot Groemer, “Special Collection on the AMADEE-18 Mars Analog Simulation”, Astrobiology, Vol. 20, No. 11, 2020. Link: https://www.liebertpub.com/doi/10.1089/ast.2020.2373 https://doi.org/10.1089/ast.2020.2373

Provided by Mary Ann Liebert

Planetary Science

Aurora-chasing citizen scientists help discover a new feature of STEVE

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In 2018, a new aurora-like discovery struck the world. From 2015 to 2016, citizen scientists reported 30 instances of a purple ribbon in the sky, with a green picket fence structure underneath. Now named STEVE, or Strong Thermal Emission Velocity Enhancement, this phenomenon is still new to scientists, who are working to understand all its details. What they do know is that STEVE is not a normal aurora – some think maybe it’s not an aurora at all – and a new finding about the formation of streaks within the structure brings scientists one step closer to solving the mystery.

Taken July 17, 2018, at Little Kenosee Lake, Saskatchewan, Canada, this photo shows the tiny green streaks below STEVE. Neil Zeller, photographer and co-author on the paper, commented “STEVE was bright and powerful for a full hour that night.” ©Copyright Neil Zeller

“Often in physics, we build our understanding then test the extreme cases or test the cases in a different environment,” Elizabeth MacDonald, a space scientist at NASA’s Goddard Space Flight Center in Greenbelt, Maryland, explains. “STEVE is different than the usual aurora, but it is made of light and it is driven by the auroral system. In finding these tiny little streaks, we may be learning something fundamentally new in how green auroral light can be produced.”

These “tiny little streaks” are extraordinarily small point-like features within the green picket fence of STEVE. In a new paper for AGU Advances, researchers share their latest findings on these points. They suggest the streaks could be moving points of light – elongated in the images due to blur from the cameras. The tip of the streak in one image will line up with the end of the tail in the next image, contributing to this speculation from the scientists. However, there are still a lot of questions to be answered – determining whether the green light is a point or indeed a line, is one extra clue to help scientists figure out what causes green light.

“I’m not entirely sure about anything with respect to this phenomenon just yet,” Joshua Semeter, a professor at Boston University and first author on the paper, said. “You have other sequences where it looks like there is a tube-shaped structure that persists from image to image and doesn’t seem to conform to a moving point source, so we’re not really sure about that yet.”

STEVE as a whole is something that scientists are still working to label. Scientists tend to classify optical features in the sky into two categories: airglow and aurora. When airglow occurs at night, atoms in the atmosphere recombine and release some of their stored energy in the form of light, creating bright swaths of color. By studying the patterns in airglow, scientists can learn more about that area of the atmosphere, the ionosphere. To be classified as an aurora, on the other hand, that release of light must be caused by electron bombardment. These features are formed differently but also look different – airglow can occur across Earth, while auroras form in a broad ring around Earth’s magnetic poles.

Two different angles of distinctive green streaks below a STEVE event on Aug. 31, 2016, near Carstairs, Alberta, Canada. Recent research about the formation of these streaks is allowing scientists to learn more about this aurora-like phenomenon. View animated GIF: https://www.nasa.gov/sites/default/files/thumbnails/image/stevemay.gif ©Copyright Neil Zeller.

“STEVE in general appears to not conform well to either one of those categories,” Semeter said. “The emissions are coming from mechanisms that we don’t fully understand just yet.”

STEVE’s purple emissions are likely a result of ions moving at a supersonic speed. The green emissions seem to be related to eddies, like the ones you might see forming in a river, moving more slowly than the other water around it. The green features are also moving more slowly than the structures in the purple emissions, and scientists speculate they could be caused by turbulence in the space particles – a brew of charged particles and magnetic field, called plasma – at these altitudes.

“We know this kind of turbulence occurs. There are people who base their entire careers on studying turbulence in the ionospheric plasma formed by very rapid flows.” Semeter said. “The evidence generally comes from radar measurements. We don’t ever have an optical signature.” Semeter suggests that when it comes to the appearance of STEVE, the flows in these instances are so extreme, that we can actually see them in the atmosphere.

“This paper is the tip of the iceberg in this new area of these tiny little pieces of the picket fence. Something we do in physics is try to chip away to increase our understanding,” MacDonald said. “This paper establishes the altitude range and some of the techniques we can use to identify these features, then they can be better resolved in other observations.”

To establish the altitude range and identify these features, the scientists extensively used photos and videos captured by citizen scientists.

“Citizen scientists are the ones who brought the STEVE phenomenon to the scientists’ attention. Their photos are typically longer time lapse than our traditional scientific observations,” MacDonald said. “Citizen scientists don’t get into the patterns that scientists get into. They do things differently. They are free to move the camera around and take whatever exposure they want.” However, to make this new discovery of the points within STEVE, photographers actually took shorter exposure photographs to capture this movement.

To get those photographs, citizen scientists spend hours in the freezing cold, late at night, waiting for an aurora – or hopefully STEVE – to appear. While data can indicate if an aurora will show up, indicators for STEVE haven’t been identified yet. However, the aurora chasers show up and take pictures anyway.

Neil Zeller, a photographer and co-author on the paper, says he didn’t originally plan to be a citizen scientist. “It was just for the beauty of it,” Zeller explained. Zeller has been involved with the discovery of STEVE from the start. He showed a picture he took of STEVE to MacDonald years ago, sparking the first research into the phenomena. Now he’s a co-author on this paper.

“It’s an honor, it really is,” Zeller said about contributing to this research. “I tend to take a step back from the scientists doing the work. I’m out there for the beauty of it and to capture these phenomena in the sky.”

This paper also made use of another valuable citizen scientist contribution – a volunteer database of STEVE observations. Michael Hunnekuhl, another author on the paper, maintains this database and has contributed to STEVE findings in the past. Hunnekuhl noticed the streaks in the photographs independently of the scientists on the paper, and his detailed record and triangulation techniques were pivotal in this research.

Zeller and other citizen scientists plan to keep taking and examining those pictures, capturing the beauty of Earth’s atmosphere, and MacDonald, Semeter, and other scientists will keep studying them, uncovering more about this new phenomenon.

Provided by NASA Goddard

Biology

What Does The Fox Say To A Puma? (Biology)

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In the high plains of the central Chilean Andes, an ecosystem consisting of only a few animal species is providing researchers with new insights into how predators coexist in the wild.

Pumas are the top predators in the study research area in the Chilean Andes. Camera trap photo by Christian Osorio. ©Christian Osorio

“The puma and the culpeo fox are the only top predators on the landscape in the Chilean Andes,” said Professor Marcella Kelly, of the College of Natural Resources and Environment. “And there isn’t a wide range of prey species, in part because the guanacos [closely related to llamas] aren’t typically found in these areas anymore due to over-hunting. With such a simplified ecosystem, we thought we could really nail down how two rival predators interact.”

Kelly worked with Christian Osorio, a doctoral student in the Department of Fish and Wildlife Conservation, and researchers from the Pontifical Catholic University of Chile to chart the locations of and potential interactions between pumas and foxes in central Chile. They focused on three axes of interaction: spatial (where the animals are on the landscape), temporal (the timing of specific activities on a given landscape), and dietary (what each species is eating).

To understand the interplay between pumas and foxes, researchers deployed 50 camera stations across two sites in central Chile, one in the Rio Los Cipreses National Reserve and another on private land where cattle and horses are raised. They also collected scat samples at both locations to analyze the diets of pumas and foxes.

The team’s findings, published in the journal Diversity, showed that while pumas and foxes overlapped significantly where they lived and what time they were active, there was little overlap in what they were eating, with the puma diet consisting primarily of a large hare species introduced from Europe, while the culpeo foxes favored smaller rabbits, rodents, and seeds. The two predator species can successfully share a landscape and hunt for food over the same nighttime hours because they are, in essence, ordering from different menus.

“It is likely that foxes have realized that when they try to hunt hares, they might run into trouble with pumas,” Osorio explained. “If they are hunting smaller mammals, the pumas don’t care, but if the foxes start targeting larger prey, the pumas will react.”

How predator species interact is a crucial question for ecologists trying to understand the dynamics that inform ecosystem balances. And while the puma has been designated a species of least concern, the animal’s populations are declining and continue to be monitored by conservationists.

“Least concern does not mean no concern,” Osorio noted. “We have laws in Chile that protect the species, but the data we have to make a conservation designation are very scattered. As we accumulate more consistent and reliable data, the puma may be reclassified as vulnerable or even endangered.”

The hares that comprise approximately 70 percent of the biomass in the puma’s diet are a nonnative species, introduced to the area by European settlers. With guanacos absent from the landscape, the puma has had to adapt its diet to survive.

With some land managers and conservationists campaigning for the removal of the introduced hare species as a way to restore the area’s native ecosystem, Kelly and Osorio note that it is important to understand that pumas would be significantly impacted by a reduction in their primary food source.

A further concern, which the two are currently researching, is the interplay between wildlife and humans. The national reserve increasingly sees visitors eager to witness big cats and foxes in their natural environment, while the sheep and cattle industries are increasingly using remote terrain for livestock cultivation.

“Pumas do occasionally kill livestock, which is a challenge we’re looking into right now,” said Kelly, an affiliate of Virginia Tech’s Fralin Life Sciences Institute. “The government would like to preserve the puma, but there are competing challenges of what kind of threat they pose to livestock and what kind of threat cattle or sheep farming poses to them.”

Understanding how two predatory species can come to coexist has the potential to provide conservationists and ecologists with better ideas for how humans and wild animals can share a landscape.

References: Christian Osorio, Ana Muñoz, Nicolás Guarda, Cristian Bonacic and Marcella Kelly, “Exotic Prey Facilitate Coexistence between Pumas and Culpeo Foxes in the Andes of Central Chile”, Diversity 2020, 12(9), 317; https://www.mdpi.com/1424-2818/12/9/317 https://doi.org/10.3390/d12090317

Provided by Virginia Tech

Medicine

Singapore Scientists Identify Potential New Biomarker To Better Personalize Cancer Therapy (Medicine)

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Researchers from Duke-NUS Medical School, Erasmus University Medical Center, Yale-NUS College and Duke University have found a potential way to predict who will respond to cancer therapies that block Wnt production, such as the novel made-in-Singapore drug ETC-159. This discovery brings the goal of personalised medicine in cancer therapy a step closer to reality.

Wnt proteins are important signalling molecules that help neighbouring cells to communicate with each other. However, when the protein is produced in excess, it causes cancers. Wnt has been implicated as a key driver of many common cancers, including colorectal and breast cancers as well as leukaemia and pancreatic cancer. Many mutations can trigger an excess activity of Wnt, and finding reliable biomarkers has been challenging.

This research, published in Cancer Research, has identified an actionable biomarker–a protein called RNF43–that is altered in a distinct class of Wnt-addicted cancers.

“RNF43 is one instance that can help us predict whether a cancer cell might be dependent on the Wnt pathway,” said Assistant Professor Babita Madan, a research in Duke-NUS’ Cancer and Stem Cell Biology programme and the corresponding author of the study. RNF43 is frequently mutated in colorectal, endometrial, mucinous ovarian, pancreatic and gastric cancers.

The drug ETC-159, which was jointly developed by Duke-NUS and the Agency for Science, Technology and Research, is a novel small molecule drug candidate that targets a range of cancers including colorectal, ovarian and pancreatic cancers. It is currently in Phase 1B human trials and was used in this pre-clinical study to determine whether cancers with RNF43 mutations would respond to Wnt inhibitor therapy.

“It has been shown in the past that RNF43 regulates cell surface Wnt receptors and RNF43 mutations could cause sensitivity to Wnt inhibitor in pancreatic cancers,” said Research Fellow Yu Jia, the first author of the study.

This study expands the landscape of actionable RNF43 mutations, opening the door for more patients to benefit from these therapies. Moving forward, the team hopes that their study can help clinicians who are involved in clinical trials for Wnt inhibitors to develop a look-up table based on the team’s list of actionable RNF43 mutations.

“This is another major step towards bringing personalised medicine to cancer patients in Singapore and across the globe,” said Professor Patrick Casey, Senior Vice-Dean of Research at Duke-NUS. “Being able to customise treatments to the unique genetic signature of a patient’s cancer will allow healthcare providers to better customise treatment plans and greatly increase the chance of real impact on the disease.”

References: Jia Yu, Permeen Akhtar Bt Mohamed Yuso, Daniëlle T.J. Woutersen, Pamela Goh, Nathan Harmston, Ron Smits, David Epstein, David M. Virshup and Babita Madan (2020). The functional landscape of patient-derived RNF43 mutations predicts sensitivity to Wnt inhibition. Cancer Research. doi: 10.1158/0008-5472.CAN-20-0957

Provided by DUKE-NUS Medical School

Uncategorized

Shining a Light On The Role Of The Genome’s Dark Matter’ In Cancer Development (Medicine)

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Singapore scientists uncover potential role of long non-coding RNAs in pancreatic cancer.

Long RNA molecules carrying DNA codes that don’t get translated into proteins have long been a mystery of the human genome. Now, scientists at Duke-NUS Medical School have found a way to systematically investigate their functions and discovered some could play a role in pancreatic cancer. Their findings, published in the journal Genome Medicine, highlight the importance of investigating long non-coding RNAs (lncRNAs) in living organisms.

CRISPRi screens to identify functional Wnt-regulated lncRNAs that are important for pancreatic cancer growth in different models. ©From Figure 4 in Liu, S., Harmston, N., Glaser, T.L. et al. Wnt-regulated lncRNA discovery enhanced by in vivo identification and CRISPRi functional validation. Genome Med 12, 89 (2020). doi:10.1186/s13073-020-00788-5

RNA had long been considered an intermediary molecule; DNA codes for RNA, which, in turn, codes for protein. More recently, scientists found that of the three billion bases in the human genome, only two per cent encode proteins. Much of the remaining 98 per cent of the genome are non-coding, and once thought to be the ‘dark matter’ of the human genome, with no known functions. Some lncRNAs, a major component of this genomic dark matter, have been shown to play key roles in diverse biological processes, ranging from development to diseases.

“By combining several advanced tools, we were able to investigate the role and function of ‘the dark matter that matters’ in pancreatic cancer,” said the study’s lead author, Mr Shiyang Liu, who is an MD/PhD student at Duke-NUS.

Specifically, the research team wanted to identify lncRNAs that were regulated by a well-known pathway called Wnt signalling. This pathway regulates many genes that code for proteins, but its influence on lncRNAs has been unclear.

Wnt signalling is known to fuel the growth of some pancreatic cancers. Turning off this pathway could not only help treat pancreatic cancer but also help researchers identify the parts of the genome that are regulated by it.

To do this, the research team turned to a ETC-159, a made-in-Singapore Wnt-suppressing drug jointly developed by Duke-NUS and the Agency for Science, Technology and Research (A*STAR), which is currently progressing through clinical trials as a treatment for a range of cancers, including pancreatic.

The scientists compared what happened to lncRNAs when ETC-159 turned off Wnt signalling in preclinical model of pancreatic cancer and in pancreatic cancer cells cultured in the laboratory. They found it changed the expression of 1,503 lncRNAs in the former but only changed the expression of half that number in the latter. This highlights the importance of studying lncRNAs within the context of a more natural environment, the researchers say.

The team then used the gene editing tool CRISPR to study what happened when the 1,503 Wnt-regulated lncRNAs were turned off in the preclinical model and in pancreatic cell cultures. Twenty-one lncRNAs were found to be able to modify pancreatic cancer cell growth in the living model, whereas only half that number were identified in the cancer cell culture tests.

“Our study provides a unique window in the largely unknown role of the dark matter of the genome that plays a functional role in pancreatic cancer, and will be a valuable resource for the scientific community studying Wnt-regulated lncRNAs in cancer,” said Professor David Virshup, director of Duke-NUS’ Cancer and Stem Cell Biology Programme, a senior co-author of the study. Prof Virshup’s seminal research on Wnts led to the development of ETC-159. “Understanding that a subset of Wnt-regulated lncRNAs can act as mediators of the oncogenic function of Wnt signalling in cancers provides potential new targets for precision cancer therapies.”

Associate Professor Enrico Petretto, from Duke-NUS’ Cardiovascular and Metabolic Disorders Programme, also a senior co-author of the study, said, “Compared with previous studies we identified twice as many lncRNAs in vivo than what you might detect in vitro, and many of these are important for cancer cell growth only in vivo, providing important clues for the development of more effective cancer treatments.”

References: Liu, S., Harmston, N., Glaser, T.L. et al. Wnt-regulated lncRNA discovery enhanced by in vivo identification and CRISPRi functional validation. Genome Med 12, 89 (2020). https://genomemedicine.biomedcentral.com/articles/10.1186/s13073-020-00788-5 https://doi.org/10.1186/s13073-020-00788-5

Provided by DUKE-NUS Medical School

Chemistry

Chemistry: How Nitrogen is Transferred by A Catalyst

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Chemists at the University of Göttingen and Goethe University Frankfurt characterize key compound for catalytic nitrogen atom transfer.

The development of new drugs or innovative molecular materials with new properties requires specific modification of molecules. Selectivity control in these chemical transformations is one of the main goals of catalysis. This is particularly true for complex molecules with multiple reactive sites in order to avoid unnecessary waste for improved sustainability. The selective insertion of individual nitrogen atoms into carbon-hydrogen bonds of target molecules is, for instance, a particularly interesting goal of chemical synthesis. In the past, these kinds of nitrogen transfer reactions were postulated based on quantum-chemical computer simulations for molecular metal complexes with individual nitrogen atoms bound to the metal. These highly reactive intermediates have, however, previously escaped experimental observation. A closely entangled combination of experimental and theoretical studies is thus indispensable for detailed analysis of these metallonitrene key intermediates and, ultimately, the exploitation of catalytic nitrogen-atom transfer reactions.

Chemists in the groups of Professor Sven Schneider, University of Göttingen, and Professor Max Holthausen, Goethe University Frankfurt, in collaboration with the groups of Professor Joris van Slagern, University of Stuttgart and Professor Bas de Bruin, University of Amsterdam, have now been able for the first time to directly observe such a metallonitrene, measure it spectroscopically and provide a comprehensive quantum-chemical characterization. To this end, a platinum azide complex was transformed photochemically into a metallonitrene and examined both magnetometrically and using photo-crystallography. Together with theoretical modelling, the researchers have now provided a detailed report on a very reactive metallonitrene diradical with a single metal-nitrogen bond. The group was furthermore able to show how the unusual electronic structure of the platinum metallonitrene allows the targeted insertion of the nitrogen atom into, for example, C-H bonds of other molecules.

Professor Max Holthausen explains: “The findings of our work significantly extend the basic understanding of chemical bonding and reactivity of such metal complexes, providing the basis for a rational synthesis planning.” Professor Sven Schneider says: “These insertion reactions allow the use of metallonitrenes for the selective synthesis of organic nitrogen compounds through catalyst nitrogen atom transfer. This work therefore contributes to the development of novel ‘green’ syntheses of nitrogen compounds.”

References: Jian Sun, Josh Abbenseth, Hendrik Verplancke, Martin Diefenbach, Bas de Bruin, David Hunger, Christian Würtele, Joris van Slageren, Max C. Holthausen, Sven Schneider: A platinum(II) metallonitrene with a triplet ground state. Nat. Chem. (2020) https://doi.org/10.1038/s41557-020-0522-4

Provided by Goethe University Frankfrut

Computer Science

Researchers Develop Ultra-fast Polymer Modulators That Can Take The Heat (Computer Science / Engineering)

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Silicon-polymer hybrid modulators capable of optical data rates of 200 Gbit/s at temperatures up to 110 °C could help reduce datacenter cooling costs.

Datacenters could benefit from lower cooling costs in part to ultra-fast electro-optic modulators developed by researchers in Japan using a polymer that is stable even at temperatures that would boil water.

Waveforms of data transmitted at 200 Gbit/s using a hybrid-polymer modulator developed by researchers in Japan and capable of operating at temperatures up to 110 °C. The signals can take one of four different levels that correspond to two bits each, resulting in three holes in the overlapping signals. ©Shiyoshi Yokoyama, Kyushu University.

Reported in the journal Nature Communications, the silicon-polymer hybrid modulators can transmit 200 gigabits of data per second at up to 110 °C and could enable optical data interconnections that are both extremely fast and reliable at high temperatures, reducing the need for cooling and expanding applications in harsh environments like rooftops and cars.

Demand for high-speed data transmission such as for high-definition media streaming has exploded in recent years, and optical communications are central to many of the necessary data connections. A critical component is the modulator, which puts data on a beam of light passing through an electro-optic material that can change its optical properties in response to an electric field.

Most modulators currently use inorganic semiconductors or crystals as the electro-optic material, but organic-based polymers have the advantages that they can be fabricated with excellent electro-optic properties at a low cost and operated at low voltages.

“Polymers have great potential for use in modulators, but reliability issues still need to be overcome for many industry applications,” explains Shiyoshi Yokoyama, professor of Kyushu University’s Institute for Materials Chemistry and Engineering and leader of the research collaboration.

One challenge is that parts of the molecules in the polymer layer must be organized through a process called poling to obtain good electro-optic properties, but this organization can be lost when the layer gets warm enough to begin softening–a point referred to as the glass transition temperature.

However, if the modulators and other components can operate rapidly and reliably even at high temperatures, datacenters could run warmer, thereby reducing their energy usage–nearly 40% of which is currently estimated to go toward cooling.

Employing a polymer they designed to exhibit superb electro-optic properties and a high glass transition temperature of 172 °C through the incorporation of appropriate chemical groups, the research team achieved ultra-fast signaling at elevated temperatures in a silicon-polymer hybrid modulator based on a Mach-Zehnder interferometer configuration, which is less sensitive to temperature changes than some other architectures.

The silicon-polymer hybrid modulator seen here as a thin, black strip was developed by researchers in Japan and can transmit data at 200 Gbit/s at temperatures up to 110 °C. Modulators able to operate quickly at such high temperatures could reduce cooling demands in datacenters and unlock applications in harsh, poorly controlled environments such as cars, airplanes, and rooftops. ©Shiyoshi Yokoyama, Kyushu University.

In the modulators, composed of multiple layers including the polymer and silicon, an incoming laser beam is split into two arms of equal length. Applying an electric field across the electro-optic polymer in one of the arms changes the optical properties such that the light wave slightly shifts. When the two arms come back together, interference between the modified and unmodified beams changes the strength of the mixed output beam depending on the amount of phase shift, thereby encoding data in the light.

Using a simple data signaling scheme of just on and off states, rates of over 100 Gbit/s were achieved, while a more complicated method using four signal levels could achieve a rate of 200 Gbit/s.

This performance was maintained with negligible changes even when operating the devices over temperatures ranging from 25 °C to 110 °C and after subjecting the devices to 90 °C heat for 100 hours, demonstrating the robustness and stability of the modulators over an extraordinarily wide range of temperatures.

“Stable operation even when the temperature fluctuates up to 110 °C is wonderful,” says Yokoyama. “This temperature range means operation in controlled environments such as datacenters, even at higher than normal temperatures, and many harsh environments where temperature is not well controlled is possible.”

The current devices are millimeter sized, making them relatively large compared to other designs, but the researchers are looking into ways to further reduce the footprint for incorporation of a dense arrays of such modulators in a small area.

“This kind of performance shows just how promising polymers are for future telecommunications technologies,” Yokoyama states.

References: Guo-Wei Lu, Jianxun Hong, Feng Qiu, Andrew M. Spring, Tsubasa Kashino, Juro Oshima, Masa-aki Ozawa, Hideyuki Nawata, and Shiyoshi Yokoyama, “High-temperature-resistant silicon-polymer hybrid modulator operating at up to 200 Gbit s-1 for energy-efficient datacentres and harsh-environment applications,” Nature Communications (2020). http://dx.doi.org/10.1038/s41467-020-18005-7 https://doi.org/10.1038/s41467-020-18005-7

Provided by Kyushu University