Tech

New organ-on-a-chip finds crucial interaction between blood, ovarian cancer tumors

image: Dr. Abhishek Jain and his team at Texas A&M are collaborating with researchers at MD Anderson Cancer Center and Rice University to develop and test their new microdevice, the ovarian tumor microenvironment-chip.

Image: 
Texas A&M Engineering

In the evolving field of cancer biology and treatment, innovations in organ-on-a-chip microdevices allow researchers to discover more about the disease outside the human body. These organs-on-chips serve as a model of the state an actual cancer patient is in, thus allowing an opportunity to finding the correct treatment before administering it to the patient. At Texas A&M University, researchers are pushing these devices to new levels that could change the way clinicians approach cancer treatment, particularly ovarian cancer.

The team has recently submitted a patent disclosure with the Texas A&M Engineering Experiment Station.

"We claim several novelties in technological design as well as biological capabilities that didn't exist in prior organs-on-chips," said Dr. Abhishek Jain, lead researcher and assistant professor in the Department of Biomedical Engineering.

Jain also has a joint appointment in the College of Medicine at Texas A&M.

Jain's device -- the ovarian tumor microenvironment-chip (OTME-Chip) -- focuses on platelets, tiny blood cells that help the body form clots to stop bleeding. The microdevice, about the size of a USB, models the properties of a tumor in the lab. Researchers then can recreate events within platelets circulating in the blood as they approach the tumor and make it more potent and metastatic.

"We are creating a platform technology using the organ-on-a-chip approach where tumor biology can be advanced, and new drugs can be identified by recreating the platelet-tumor and platelet-tumor-drug interactions under the influence of flow, supporting blood vessels and the extracellular matrix," Jain said.

Ovarian cancer is a particularly challenging one to monitor. Tumors generally form deep inside a patient's tissue, and it can be difficult to obtain real-time information of the tumor's properties and how it is interacting with blood cells. Also, ovarian tumors can quickly spread inside the body, making time another vital factor in mapping the disease's progression.

The OTME-Chip builds on the current clinically observed understanding of how blood platelets move inside tumor tissue and what triggers them to spread outside the tumor. However, the actual mechanism behind this process remains mostly unknown, until now.

"For the first time, we identified a crucial interaction between platelets and the tumor via their surface proteins," Jain said. "By applying high-resolution imaging, advanced cell and molecular readouts and RNA sequencing methods leveraging the OTME-Chip, we discovered the actual genetic signaling pathways behind the blood cell triggered metastasis of ovarian cancer and a new drug strategy to stop this process."

Jain's team in College Station for this research includes postdoctoral researcher Dr. Biswajit Saha and doctoral students Jim Tronolone and Tanmay Mathur. Their research involving the OTME-Chip was recently published in the journal Science Advances.

Jain said the OTME-Chip has several applications, both in observing how cancer cells interact differently with vascular and blood cells and testing novel ways to treat the disease that may complement chemotherapy and radiotherapy of tumors.

"This multimodal OTME-Chip is going to provide an ideal platform to the health care researchers to evaluate their anti-cancer, vascular and hematological drugs individually or in combination in an artificially created human-level tumor microenvironment," Jain said.

Jain collaborates with Dr. Anil Sood, professor and vice chair for translational research in the Departments of Gynecologic Oncology and Cancer Biology at MD Anderson Cancer Center. The team also works with Dr. Gang Bao, a gene editing expert from Rice University.

"Sood is a leader in the ovarian cancer field," Jain said. "He has been a fantastic collaborator and has provided us access to patient tissue and blood samples needed to validate the findings from our chip, which brings us very close to initiating new clinical trials."

Credit: 
Texas A&M University

Comprehensive clinical sequencing opens door to the promise of precision medicine

image: Co-corresponding author Kim Nichols, M.D., St. Jude Cancer Predisposition Division director, demonstrated that comprehensive genomic sequencing of all pediatric cancer patients is feasible and essential to capitalize on the lifesaving potential of precision medicine.

Image: 
St. Jude Children's Research Hospital

St. Jude Children's Research Hospital investigators have demonstrated that comprehensive genomic sequencing of all pediatric cancer patients is feasible and essential to capitalize on the lifesaving potential of precision medicine. Results from the St. Jude Genomes for Kids study appear online today in the journal Cancer Discovery.

Whole genome and whole exome sequencing of germline DNA was offered to all 309 patients who enrolled in the study. Whole genome, whole exome and RNA sequencing of tumor DNA was carried out for the 253 patients for whom adequate tumor samples were available.

Overall, 86% of patients had at least one clinically significant variation in tumor or germline DNA. Those included variants related to diagnosis, prognosis, therapy or cancer predisposition. Researchers estimated that 1 in 5 patients had clinically relevant mutations that would have gone undetected using standard sequencing methods.

"Some of the most clinically relevant findings were only possible because the study combined whole genome sequencing with whole exome and RNA sequencing," said Jinghui Zhang, Ph.D., St. Jude Department of Computational Biology chair and co-corresponding author of the study.

Every tumor is unique. Every patient is unique.

Comprehensive clinical sequencing that includes whole genome, whole exome and RNA sequencing is not widely available. But as the technology becomes less expensive and accessible to more patients, researchers said comprehensive sequencing will become an important addition to pediatric cancer care.

"We want to change the thinking in the field," said David Wheeler, Ph.D., St. Jude Precision Genomics team director and a co-author of the study. "We showed the potential to use genomic data at the patient level. Even in common pediatric cancers, every tumor is unique, every patient is unique.

"This study showed the feasibility of identifying tumor vulnerabilities and learning to exploit them to improve patient care," he said.

Tumor sequencing guided the change in treatment for 12 of the 78 study patients for whom standard of care was unsuccessful. In four of the 12 patients, the changes stabilized disease and extended patient lives. Another patient, one with acute myeloid leukemia, went into remission and was cured by blood stem cell transplantation.

"Through the comprehensive genomic testing in this study, we were able to clearly identify tumor variations that could be treated with targeted agents, opening doors for how oncologists manage their patients," said co-corresponding author Kim Nichols, M.D., St. Jude Cancer Predisposition Division director.

Additional findings and details

Genomes for Kids enrolled patients between August 2015 and March 2017.

Eighteen percent of patients carried germline variations in one of 156 known, cancer-predisposition genes.

Almost two-thirds of the germline variations identified would not have been detected based on current screening guidelines.

Next steps

Genomes for Kids helped launch the hospital's clinical genomics program, which has enrolled about 2,700 cancer patients to date.

Meanwhile, data generated through the Genomes for Kids study are available at no cost to the international research community. By sharing the data, St. Jude aims to speed advances in understanding and treatment of pediatric cancer. The data are available in St. Jude Cloud.

"Even the most treatable cancers are not curable in all patients. For example, relapse remains the leading cause of death for the most common childhood cancer, acute lymphoblastic leukemia," Nichols said. "Being able to understand and predict which patients will respond to treatment and which won't requires collecting comprehensive genomic data on all patients."

Credit: 
St. Jude Children's Research Hospital

Study shows cancer misinformation common on social media sites

image: Skyler Johnson, MD

Image: 
Huntsman Cancer Institute

A new study published online today in the Journal of the National Cancer Institute reports that one third of the most popular cancer treatment articles on social media contain misinformation. Further, the vast majority of that misinformation has the potential to harm cancer patients by supporting approaches that could negatively impact the quality of their treatment and chances for survival. The study also showed that articles containing misinformation garner more attention and engagement than articles with evidence-based information.

The internet is a major source for health information, and misinformation is growing among many types of health conditions. This is an urgent challenge because it can result in patients making decisions detrimental to their survival or outcomes.

Skyler Johnson, MD, Huntsman Cancer Institute (HCI) physician-scientist and assistant professor of radiation oncology at the University of Utah (U of U), headed the study. Johnson's interest in this area was piqued after work he completed earlier in his career showed higher risk of death among patients who used unproven approaches to treat cancer as an alternative to conventional, evidence-based treatments. That research led Johnson to several discussions with patients, physicians, researchers, and journalists. In the course of these conversations, Johnson found a recurring theme about the role that online media, particularly social media, played in disseminating inaccurate cancer information. Further, in his clinical practice at HCI where he cares for people with cancer, Johnson often heard from patients who had questions about articles they saw on social media.

He and the research team set out to better understand the quantity and nature of cancer information on social media. The research team included experts in cancer care, health outcomes, and communications. They convened medical expert panels to review and assess the claims presented in 200 of the most popular articles on social media sites. For this study, the researchers focused on articles related to breast, prostate, lung, and colorectal cancers.

"We found misinformation is clearly prevalent in cancer articles on social media, and the vast majority of those pieces contain harmful information," says Johnson.

The team's findings showed just how common it is for cancer patients to receive misinformation. Of 200 articles analyzed, 33% contained misinformation. Of those, 77% contained information that could negatively influence patient outcomes. Johnson noted that after reviewing articles, he has major concerns about how one could distinguish between which articles are reliable and which are not.

Johnson says he understands why patients seek information online, including through social media platforms. "Having cancer is a unique and vulnerable situation. Patients are dealing with a new disease. They want to feel in control over their own health and do everything possible to maintain hope. They experience a deluge of new information as they are diagnosed, including through social media. Some patients seek out information, and some information is shared with patients by well-intentioned family and friends."

He advocates for physicians to maintain open communication channels with their patients. In his practice, he lets patients know they are likely to encounter misinformation about their cancer online. He encourages his patients to talk to him if they have questions about information they see related to their cancer online or through social media.

Johnson hopes that this research is just the start. He wants to identify predictors of misinformation and harm on social media in order to help physicians and patients better understand and navigate this challenging issue.

"We need to address these issues head on," Johnson says. "As a medical community, we can't ignore the problem of cancer misinformation on social media or ask our patients to ignore it. We must empathize with our patients and help them when they encounter this type of information. My goal is to help answer their questions, and provide cancer patients with accurate information that will give them the best chance for the best outcome."

Credit: 
Huntsman Cancer Institute

Sharks, lies, and videotape: Scientists document problems with Shark Week

image: Tiger Shark At Tigerbeach Bahamas

Image: 
Marion Kraschl, CC BY 3.0 https://creativecommons.org/licenses/by/3.0, via Wikimedia Commons

MEADVILLE, PA - July 22, 2021 - Shark Week is many things. First and foremost, it's a week of shark-themed documentary programming on the Discovery Channel. Now in its 33rd year, it's the longest-running cable event in history. It's the biggest audience that marine biologists and ocean conservationists get, attracting millions of viewers who might otherwise not ever think about sharks at all. It's a stage that has launched careers of shark scientists and inspired many others to pursue jobs as ocean scientists.

However, a new analysis shows that Shark Week is also deeply flawed in ways that undermine its goals, potentially harming both sharks and shark scientists. To document just how pervasive these issues are, a team of researchers performed a content and discourse analysis of more than 200 Shark Week episodes.

"The public's perception of sharks, shark science, and shark scientists is heavily influenced by Shark Week. Unfortunately, we found that Shark Week programming focuses on negative portrayals of sharks and does not often accurately portray shark research nor the diversity of expertise in the field. While critics have been saying this for some time, we now have the numbers to back it up," said lead author Dr. Lisa Whitenack, associate professor of biology and geology at Allegheny College.

Key findings of the analysis include:

Though many shows ostensibly focused on scientific research, they often relied on non-scientist hosts using atypical methods to answer a question long answered by the scientific community. Many of these methods border on wildlife harassment, and some are far over that line. Certain repeat hosts regularly said things that were demonstrably false about the biology, behavior, or conservation of sharks.

Despite many shows taking place in South Africa, the Bahamas, or Mexico, only a handful of non-white experts were ever featured in the show's 30-plus year run, including many examples of bringing white American hosts with no relevant expertise halfway around the world for a show instead of involving local experts. Of the hosts and experts featured in more than 10 episodes, 100 percent were white men. Of the hosts and experts featured in more than five episodes, there were more men who were non-scientists named "Mike" than there were women of any name or occupation. Many women and people of color work in the field and have never been featured.

Narration regularly contained staggering examples of needlessly promoting fear. Even Shark Week episode titles promote fear and sensationalism, such as "Sharkpocalypse," "Deadly Stripes," "Great White Serial Killer," and "Sharks: Are They Hunting Us?".

Despite frequent claims from the Discovery Channel that Shark Week promotes conservation, the authors identified just six specific and detailed mentions of anything related to how Shark Week's massive audience could help sharks. Additionally, the three most commonly featured species are not any of the species of greatest conservation concern, and most critically endangered species have never been featured at all.

The authors document numerous other issues with Shark Week and also suggest specific actionable solutions to improve for the future.

"We know that media representation and access to role models can play an important part in how welcoming STEM fields are to scientists from historically excluded groups. Moving away from featuring largely white male experts and towards including more diverse scientific voices and perspectives, particularly those of local experts where episodes are being filmed, would be a valuable step forward for Shark Week and shark science," said co-author Dr. Catherine Macdonald, lecturer at the Rosenstiel School of Marine and Atmospheric Science, University of Miami, and director of Field School.

"Shark Week attracts an audience of millions of people. As a public science educator, I can't even imagine how much good they could do if they tried, even a little, to share factually accurate and useful information about shark science and conservation. As it is, Shark Week is an enormous missed opportunity," said senior author Dr. David Shiffman of Arizona State University's New College of Interdisciplinary Arts and Sciences.

Credit: 
Allegheny College

Martian global dust storm ended winter early in the south

video: Side-by-side movies show how the 2018 global dust storm enveloped the Red Planet, courtesy of the Mars Color Imager (MARCI) camera onboard NASA's Mars Reconnaissance Orbiter (MRO).

Image: 
NASA/JPL-Caltech/MSSS.

A dust storm that engulfed Mars in 2018 destroyed a vortex of cold air around the planet's south pole and brought an early spring to the hemisphere. By contrast, the storm caused only minor distortions to the polar vortex in the northern hemisphere and no dramatic seasonal changes. Dr Paul Streeter of The Open University's Faculty of Science, Technology, Engineering and Mathematics will present the work today (23 July) at the virtual National Astronomy Meeting (NAM 2021).

Over two weeks at the beginning of June 2018, localised dust storms combined and spread to form an impenetrable blanket of dust that hid almost the entire planet's surface. The global dust storm, which coincided with Mars's equinox and lasted until mid-September, proved fatal to NASA's solar-powered Opportunity rover.

Streeter and colleagues from The Open University, NASA and the Russian Academy of Sciences examined the effects of the event on the martian atmosphere by combining data from a Mars Global Climate Model with observations from the European Space Agency/Roscosmos ExoMars Trace Gas Orbiter and NASA's Mars Reconnaissance Orbiter missions.

Dr Streeter said: "This was a perfect opportunity to investigate how global dust storms impact the atmosphere at the martian poles, which are surrounded by powerful jets of wind in winter. Since the last global storm in 2007, several new missions and instruments have arrived in Mars orbit, so the 2018 event was the most-observed to date."

Previous research has shown that high levels of dust in the atmosphere can have significant effects on polar temperatures and winds. The vortices at the winter poles also affect temperatures and the transport of air, dust, water and chemicals, so their disruption could mean substantial changes in the martian atmosphere.

The team found that the 2018 storm had profoundly different effects in each hemisphere. At the south pole, where the vortex was almost destroyed, temperatures rose and wind speeds fell dramatically. While the vortex may have already been starting to decay due to the onset of spring, the dust storm appears to have had a decisive effect in ending winter early.

The northern polar vortex, by contrast, remained stable and the onset of autumn followed its usual pattern. However, the normally elliptical northern vortex was changed by the storm to become more symmetrical. The researchers link this to the high dust content in the atmosphere suppressing atmospheric waves caused by the extreme topography in the northern hemisphere, which has volcanoes over twice as tall as Mount Everest and craters as deep as terrestrial mountains.

Dr Streeter added: "Global dust storms at equinox may enhance transport into the southern pole due to the diminished vortex, while the more robust northern vortex continues to act as an effective barrier. If this pattern for global dust storms holds over the course of the thousands of years that Mars maintains this particular axial tilt, it has implications for how dust is deposited at the north and south poles and our understanding of the planet's climate history."

Credit: 
Royal Astronomical Society

Trash-bin foragers: Innovation and spread of complex culture in suburban parrots

In the suburbs of Sydney, Australia, sulphur-crested cockatoos routinely loot lidded household waste bins to scavenge for food. In a new study, researchers document the emergence and geographic spread of innovative bin-opening behaviors in urban parrot populations, revealing the presence of a complex social learning culture in these birds. What's more, this behavior appears to have emerged as a direct response to land-use change and urbanization, demonstrating how animal cultures could allow for local adaptation of urban animal populations in the Anthropocene. In animals, ecological novelty, including novelties unique to anthropogenic urban landscapes, can lead to cultural innovation. Generally, culture in animals involves socially learned behaviors shared among peers and between generations in a group of animals. While a variety of cultures have been observed across social species with complex cognition, identifying persistent cultures and social learning in animal species remains challenging. Recently, the sulpher-crested cockatoo, a large-brained and highly social parrot that's become increasingly common in the cities of eastern Australia, has been observed opening household waste bins to scavenge food. While this emergent and innovative foraging behavior exploits a widely available resource unique to urban environments, whether or not it represents social learning or culture in cockatoo foraging behavior remains unknown. Barbara Klump and colleagues used a large-scale citizen science survey to map cockatoo bin opening across the greater Sydney region. According to the findings, before 2018, bin foraging was reported in only three suburbs. By late 2019, however, it had spread to 44 via social learning. Analysis of 160 direct observations of the behavior revealed distinct styles and suburb-specific approaches to how the birds opened the bins. Klump et al. describe how the innovation, spread and emergence of regional variation in this novel foraging behavior illustrate the existence of cultural complexity in this group of birds.

Credit: 
American Association for the Advancement of Science (AAAS)

Mars: Scientists determine crustal thickness

image: The two largest quakes detected by NASA's InSight appear to have originated in a region of Mars called Cerberus Fossae. Scientists previously spotted signs of tectonic activity here, including landslides. This image was taken by the HiRISE camera on NASA's Mars Reconnaisance Orbiter.

Image: 
NASA/JPL-Caltech/University of Arizona

Based on the analysis of marsquakes recorded by NASA's InSight mission, the structure of Mars's crust has now been determined in absolute numbers for the first time. Beneath the InSight landing site, the crust is either approximately 20 or 39 kilometres thick. That is the result of an international research team led by geophysicist Dr Brigitte Knapmeyer-Endrun at the University of Cologne's Institute of Geology and Mineralogy and Dr Mark Panning at Jet Propulsion Laboratory, California Institute of Technology (Caltech). InSight stands for 'Interior Exploration using Seismic Investigations, Geodesy and Heat Transport'. NASA's lander, which landed on Mars on 26 November 2018, explores the crust, mantle and core of the red planet. The paper 'Thickness and structure of the Martian crust from InSight seismic data' will appear in Science on July 23.

In the past, only relative differences in the thickness of Mars's could be estimated, and additional assumptions were required to obtain absolute thicknesses. The resulting absolute values thus showed large scatter, depending on which assumptions were made. Seismology now replaces these assumptions with a direct measurement at the landing site, and thus calibrates the crustal thickness for the entire planet. This independent data point also allows estimating the density of the crust.

'What seismology can measure are mainly velocity contrasts. These are differences in the propagation velocity of seismic waves in different materials,' said Knapmeyer-Endrun, lead author of the paper. 'Very similar to optics, we can observe phenomena like reflection and refraction. Regarding the crust, we also benefit from the fact that crust and mantle are made of different rocks, with a strong velocity jump between them.' Based on these jumps, the crust's structure can be determined very precisely.

The data show that at the InSight landing site, the top layer is about 8 (+/-2) kilometres thick. Below that, another layer follows to about 20 (+/-5) kilometres. 'It is possible that the mantle starts under this layer, which would indicate a surprisingly thin crust, even compared to the continental crust on Earth. Beneath Cologne, for example, the Earth's crust is about 30 kilometres thick,' Knapmeyer-Endrun explained. Possibly, however, there is a third crustal layer on Mars, which would make the Martian crust under the landing site about 39 (+/-8) kilometres thick. That would be more consistent with previous findings, but the signal from this layer is not essential to match existing data. 'In both cases, however, we can rule out the possibility that the entire crust is made of the same material known from surface measurements and from Martian meteorites,' the geophysicist said. 'Rather, the data suggest that the uppermost layer is composed of an unexpectedly porous rock. Also, there could be other rock types at greater depths than the basalts seen at the surface.'

The single, independent measurement of crustal thickness at the InSight landing site is sufficient to map the crust across the entire planet. Measurements from satellites orbiting Mars provide a very clear picture of the planet's gravity field, allowing the scientists to compare relative differences in crustal thickness to the measurement taken at the landing site. The combination of these data provides an accurate map.

The crustal thickness of Mars is particularly interesting because the crust formed at an early formation stage from the remnants of a molten mantle. Thus, data on its present-day structure can also provide information on how Mars evolved. In addition, a more precise understanding of the evolution of Mars helps to decipher how early differentiation processes unfolded in the solar system and why Mars, Earth, and other planets are so different today.

Credit: 
University of Cologne

DeepMind and EMBL release the most complete database of predicted 3D structures of human proteins

image: Protein structures to represent the data obtained via AlphaFold

Image: 
Karen Arnott/EMBL-EBI

LONDON, 22 July 2021 - DeepMind today announced its partnership with the European Molecular Biology Laboratory (EMBL), Europe's flagship laboratory for the life sciences, to make the most complete and accurate database yet of predicted protein structure models for the human proteome. This will cover all ~20,000 proteins expressed by the human genome, and the data will be freely and openly available to the scientific community. The database and artificial intelligence system provide structural biologists with powerful new tools for examining a protein's three-dimensional structure, and offer a treasure trove of data that could unlock future advances and herald a new era for AI-enabled biology.

AlphaFold's recognition in December 2020 by the organisers of the Critical Assessment of protein Structure Prediction (CASP) benchmark as a solution to the 50-year-old grand challenge of protein structure prediction was a stunning breakthrough for the field. The AlphaFold Protein Structure Database builds on this innovation and the discoveries of generations of scientists, from the early pioneers of protein imaging and crystallography, to the thousands of prediction specialists and structural biologists who've spent years experimenting with proteins since. The database dramatically expands the accumulated knowledge of protein structures, more than doubling the number of high-accuracy human protein structures available to researchers. Advancing the understanding of these building blocks of life, which underpin every biological process in every living thing, will help enable researchers across a huge variety of fields to accelerate their work.

Last week, the methodology behind the latest highly innovative version of AlphaFold, the sophisticated AI system announced last December that powers these structure predictions, and its open source code were published in Nature. Today's announcement coincides with a second Nature paper that provides the fullest picture of proteins that make up the human proteome, and the release of 20 additional organisms that are important for biological research.

"Our goal at DeepMind has always been to build AI and then use it as a tool to help accelerate the pace of scientific discovery itself, thereby advancing our understanding of the world around us," said DeepMind Founder and CEO Demis Hassabis, PhD. "We used AlphaFold to generate the most complete and accurate picture of the human proteome. We believe this represents the most significant contribution AI has made to advancing scientific knowledge to date, and is a great illustration of the sorts of benefits AI can bring to society."

AlphaFold is already helping scientists to accelerate discovery

The ability to predict a protein's shape computationally from its amino acid sequence - rather than determining it experimentally through years of painstaking, laborious and often costly techniques - is already helping scientists to achieve in months what previously took years.

"The AlphaFold database is a perfect example of the virtuous circle of open science," said EMBL Director General Edith Heard. "AlphaFold was trained using data from public resources built by the scientific community so it makes sense for its predictions to be public. Sharing AlphaFold predictions openly and freely will empower researchers everywhere to gain new insights and drive discovery. I believe that AlphaFold is truly a revolution for the life sciences, just as genomics was several decades ago and I am very proud that EMBL has been able to help DeepMind in enabling open access to this remarkable resource."

AlphaFold is already being used by partners such as the Drugs for Neglected Diseases Initiative (DNDi), which has advanced their research into life-saving cures for diseases that disproportionately affect the poorer parts of the world, and the Centre for Enzyme Innovation (CEI) is using AlphaFold to help engineer faster enzymes for recycling some of our most polluting single-use plastics. For those scientists who rely on experimental protein structure determination, AlphaFold's predictions have helped accelerate their research. For example, a team at the University of Colorado Boulder is finding promise in using AlphaFold predictions to study antibiotic resistance, while a group at the University of California San Francisco has used them to increase their understanding of SARS-CoV-2 biology.

The AlphaFold Protein Structure Database

The AlphaFold Protein Structure Database* builds on many contributions from the international scientific community, as well as AlphaFold's sophisticated algorithmic innovations and EMBL-EBI's decades of experience in sharing the world's biological data. DeepMind and EMBL's European Bioinformatics Institute (EMBL-EBI) are providing access to AlphaFold's predictions so that others can use the system as a tool to enable and accelerate research and open up completely new avenues of scientific discovery.

"This will be one of the most important datasets since the mapping of the Human Genome," said EMBL Deputy Director General, and EMBL-EBI Director Ewan Birney. "Making AlphaFold predictions accessible to the international scientific community opens up so many new research avenues, from neglected diseases to new enzymes for biotechnology and everything in between. This is a great new scientific tool, which complements existing technologies, and will allow us to push the boundaries of our understanding of the world."

In addition to the human proteome, the database launches with ~350,000 structures including 20 biologically-significant organisms such as E.coli, fruit fly, mouse, zebrafish, malaria parasite and tuberculosis bacteria. Research into these organisms has been the subject of countless research papers and numerous major breakthroughs. These structures will enable researchers across a huge variety of fields - from neuroscience to medicine - to accelerate their work.

The future of AlphaFold

The database and system will be periodically updated as we continue to invest in future improvements to AlphaFold, and over the coming months we plan to vastly expand the coverage to almost every sequenced protein known to science - over 100 million structures covering most of the UniProt reference database.

To learn more, please see the Nature papers describing our full method and the human proteome*, and read the Authors' Notes*. See the open-source code to AlphaFold if you want to view the workings of the system, and Colab notebook* to run individual sequences. To explore the structures, visit EMBL-EBI's searchable database* that is open and free to all.

Credit: 
European Molecular Biology Laboratory - European Bioinformatics Institute

Eyes wide shut: How newborn mammals dream the world they're entering

As a newborn mammal opens its eyes for the first time, it can already make visual sense of the world around it. But how does this happen before they have experienced sight?

A new Yale study suggests that, in a sense, mammals dream about the world they are about to experience before they are even born.

Writing in the July 23 issue of Science, a team led by Michael Crair, the William Ziegler III Professor of Neuroscience and professor of ophthalmology and visual science, describes waves of activity that emanate from the neonatal retina in mice before their eyes ever open.

This activity disappears soon after birth and is replaced by a more mature network of neural transmissions of visual stimuli to the brain, where information is further encoded and stored.

"At eye opening, mammals are capable of pretty sophisticated behavior," said Crair, senior author of the study, who is also vice provost for research at Yale." But how do the circuits form that allow us to perceive motion and navigate the world? It turns out we are born capable of many of these behaviors, at least in rudimentary form."

In the study, Crair's team, led by Yale graduate students Xinxin Ge and Kathy Zhang, explored the origins of these waves of activity. Imaging the brains of mice soon after birth but before their eyes opened, the Yale team found that these retinal waves flow in a pattern that mimics the activity that would occur if the animal were moving forward through the environment.

"This early dream-like activity makes evolutionary sense because it allows a mouse to anticipate what it will experience after opening its eyes, and be prepared to respond immediately to environmental threats," Crair noted.

Going further, the Yale team also investigated the cells and circuits responsible for propagating the retinal waves that mimic forward motion in neonatal mice. They found that blocking the function of starburst amacrine cells, which are cells in the retina that release neurotransmitters, prevents the waves from flowing in the direction that mimics forward motion. This in turn impairs the development of the mouse's ability to respond to visual motion after birth.

Intriguingly, within the adult retina of the mouse these same cells play a crucial role in a more sophisticated motion detection circuit that allows them to respond to environmental cues.

Mice, of course, differ from humans in their ability to quickly navigate their environment soon after birth. However, human babies are also able to immediately detect objects and identify motion, such as a finger moving across their field of vision, suggesting that their visual system was also primed before birth.

"These brain circuits are self-organized at birth and some of the early teaching is already done," Crair said. "It's like dreaming about what you are going to see before you even open your eyes."

Credit: 
Yale University

HKU scientists harness the naturally abundant CRISPR-Cas system to edit superbugs with the hope of treating infections caused by drug resistant pathogens

image: An illustration of the strategies and workflow of the transferrable type I CRISPR Cascade-mediated editing of the superbug P. aeruginosa.

Image: 
The University of Hong Kong

A research team led by Dr Aixin YAN, Associate Professor from the Research Division for Molecular & Cell Biology, Faculty of Science, in collaboration with Honorary Clinical Professor Patrick CY WOO from the Department of Microbiology, Li Ka Shing Faculty of Medicine, the University of Hong Kong (HKU), reported the development of a transferrable and integrative type I CRISPR-based platform that can efficiently edit the diverse clinical isolates of Pseudomonas aeruginosa, a superbug capable of infecting various tissues and organs and a major source of nosocomial infections. The technique can accelerate the identification of resistance determinants of multidrug resistant (MDR) pathogens and the development of novel anti-resistance strategies.

The research opened a new avenue to genomically edit those wild bacterial species and isolates, such as those with clinical and environmental significance and those forming human microbiome. It also provided a framework to harness other CRISPR-Cas systems widespread in prokaryotic genomes and expand the CRISPR-based toolkits. The research has been published in the leading science journal Nucleic Acids Research.

Background

CRISPR-Cas system comprises the adaptive immune system in prokaryotes that disarms invading viruses by cleaving their DNA. Owing to its unique capability of targeting and altering DNA sequences, CRISPR-Cas has been exploited as the next-generation genome editing method. The method is based on the Class 2 type II CRISPR/Cas9 system, which has revolutionised genetics and biomedical research in a plethora of organisms and was awarded the 2020 Nobel Prize in Chemistry. However, the Class 2 CRISPR-Cas systems represent only ?10% of the CRISPR-Cas systems encoded naturally in prokaryotes. Their applications to edit bacterial genomes are rather limited.

Remarkably, CRISPR-Cas systems belonging to different classes and types are continuously identified, and they serve as a deep reservoir for the expansion of the CRISPR-based toolkits. The most diverse and widely distributed CRISPR-Cas systems is the type I system which accounts for 50% of all CRISPR-Cas systems identified and has the potential to expand the CRISPR-based toolkits with distinctive advantages not accessible with the class 2 systems, such as high specificity, minimal off-targeting, and capable of large fragment deletions. However, type I CRISPR-Cas system hinges on a multi-component effector complex termed as Cascade to interfere DNA which is not readily transferrable to heterologous hosts, hindering the widespread application of these naturally abundant CRISPR for genome editing and therapeutics.

Key findings

Previously, the team has identified a highly active type I-F CRISPR-Cas system in a clinical multidrug resistant P. aeruginosa strain PA154197 which was isolated from a bloodstream infection case in Queen Mary Hospital. They characterised this CRISPR-Cas system and successfully developed a genome-editing method applicable in the MDR isolate based on this native type I-F CRISPR-Cas system. The method enabled rapid identification of the resistance determinants of the MDR clinical isolate and the development of a novel anti-resistance strategy (Cell Reports, 2019, 29, 1707-1717).

To overcome the barrier of transferring the complex type I Cascade to heterologous hosts, in this study, the team cloned the entire type I-F cas operon into an integration proficient vector mini-CTX and delivered the cassette into heterologous hosts by conjugation, a DNA transfer approach common in nature. The mini-CTX vector enabled the integration of the entire Cascade onto the conserved attB genetic locus in the genome of the heterologous hosts, enabling them to harbour a "native" type I-F CRISPR-Cas system that can be stably expressed and function. The team showed that the transferred type I-F Cascade displays a significantly greater DNA interference capacity and higher strain stability than the transferrable Cas9 system and can be employed for genome editing with efficiency (>80%) and simplicity, i.e. by a one-step transformation of a single editing plasmid.

Furthermore, they developed an advanced transferrable system that includes both a highly active type I-F Cascade and a recombinase to promote the application of the system in strains with a poor homologous recombination capacity, wild P. aeruginosa isolates without genome sequence information, and in other Pseudomonas species. Lastly, the introduced type I-F Cascade genes can be readily removed from the host genomes through the I-F Cascade-mediated deletion of large DNA fragments, resulting in scarless genome editing in the host cells. The application of the transferrable system for gene repression was also demonstrated, highlighting the robust and diverse applications of the developed transferrable type I-F CRISPR system.

Dr Aixin Yan predicted that this novel method will be extended to editing not only pathogens but also microbiome to promote human health, she said: "We believe that CRISPR-based technology and therapies will bring new hopes to combatting superbugs in the future."

Credit: 
The University of Hong Kong

NTU Singapore scientists develop tougher, safer bicycle helmets using new plastic material

image: (from L-R) Research associate Goram Gohel, Associate Professor Leong Kah Fai and research fellow Dr Bhudolia Somen Kumar, from NTU's from the School of Mechanical and Aerospace Engineering, with their composite bicycle helmet prototype.

Image: 
NTU Singapore

As cities worldwide expand their networks of cycling paths and more cyclists take to the streets, the chances of cycling accidents and potential collisions increase as well, underscoring the need for proper cycling safety in dense urban areas.

According to a World Health Organisation report in 2020, more than 60 per cent of the reported bicycle-related deaths and long-term disabilities are a result of accidents with head injuries.

Researchers from Nanyang Technological University, Singapore (NTU Singapore), in collaboration with French specialty materials leader Arkema, have developed a tougher, safer bicycle helmet using a combination of materials. The new helmet prototype has higher energy absorption, reducing the amount of energy transferred to a cyclist's head in the event of an accident and lowering the chances of serious injury.

Led by Associate Professor Leong Kah Fai from the School of Mechanical and Aerospace Engineering, the team, comprising research fellow Dr Bhudolia Somen Kumar, research associate Goram Gohel and MSc student Elisetty Shanmuga, created the composite helmet with an outer shell made primarily of a new type of acrylic thermoplastic resin, reinforced with carbon fibre.

The new thermoplastic resin, named Elium®, was developed by Arkema, one of NTU's industry partners. The NTU team worked with Arkema engineers to develop a moulding process for Elium® to manufacture stronger bicycle helmets.

"Our partnership with Arkema is driven by the desire to develop a new type of helmet that is stronger and safer for cyclists," said Assoc Prof Leong. "Helmets have been proven time and time again to play a critical role in reducing the severity of injuries and number of fatalities. Our prototype helmet has been subjected to a barrage of internationally benchmarked tests and has demonstrated the ability to provide greater protection for cyclists compared to conventional helmets."

The findings by the research team were published in the peer-reviewed journal Composites Part B: Engineering in May.

Tougher, stiffer outer shell absorbs more energy

Bicycle helmets are made up of two components. The first is an outer shell, usually made from a mass-produced plastic like polycarbonate. Beneath it is a layer of expanded polystyrene foam - the same material used in product packaging and takeaway boxes.

The outer shell is designed to crack on impact in order to dissipate energy across the entire surface of the helmet. The foam layer then compresses and absorbs the bulk of impact energy so that less energy is transferred to the head.

The team's composite helmet replaces the conventional polycarbonate outer shell with one using Elium® reinforced with carbon fibre.

This reinforcement makes the outer shell tougher, stiffer, and less brittle than a polycarbonate shell. It also increases the helmet's contact time, which is the total time of impact in which the helmet experiences impact load.

These properties allow the outer shell to absorb more impact energy over a longer period, while also dissipating it evenly throughout the helmet. This results in less overall force reaching the head, thereby reducing the chances of critical injury.

"When the helmet hits a surface at high speed, we noticed that there is a deformation along with the spread failure of the composite shell, which means the outer shell is taking more load and absorbing more energy," said Dr Somen. "This is what you really want - the more impact absorbed by the shell, the less of it that reaches the foam, and so there is less overall impact to the head. We found that in existing polycarbonate helmets, about 75 per cent of the energy is absorbed by the foam. This is not ideal as the foam is in direct contact with the human head."

In contrast, the team's composite helmet shell absorbed over 50 per cent of impact energy, leaving the foam to absorb much less energy at about 35 per cent.

Safety forged on the anvils of NTU

The researchers tested their helmets by driving them down at high speeds on three different types of anvils - flat, hemispherical (rounded), and curbstone (pyramid-shaped) - to simulate different road conditions.

These are the same tests used for the U.S. Consumer Product Safety Commission standard (CPSC 1203) certification, an internationally recognised safety standard for helmets. The team's helmet prototype meets all CPSC 1203 guidelines.

The researchers paid particular attention to peak acceleration forces, which is a measure of how much force a helmet takes based on how fast it is moving at the point of impact. A helmet must have a peak acceleration of less than 300G (g-force) to be deemed fit for use under CPSC 1203, with lower g-force values being safer.

On two flat anvil tests, the researchers' helmets performed on par with a control polycarbonate helmet, producing results of 194.7G and 197.2G to the control's 195.4G and 198.2G.

However, tests on the hemispherical and curbstone anvils showed substantial improvements of the team's composite helmet over the polycarbonate one. On two hemispherical anvil tests, the composite helmet recorded 100.9G and 103.1G, while the control helmet had a much higher peak acceleration of 173G and 178.7G.

On a single curbstone anvil test, the researchers' helmets recorded 111.7G, a notable improvement over the reference helmet that produced a result of 128.7G.

The researchers referred to the most widely used injury metric called the Head Injury Criterion (HIC) to calculate the probability of serious injury and fatality while using the helmet. HIC values are derived from a combination of peak acceleration values and the duration of acceleration.

The team's analysis of the flat anvil test results and the HIC showed that the composite helmet could potentially reduce critical and fatal injury rates from 28.7 per cent and 6 per cent to 16.7 per cent and 3 per cent respectively, compared to a polycarbonate helmet.

Even though peak acceleration was roughly equal between both types of helmets, the composite helmet's tougher outer shell led to longer duration of acceleration during impact. This allows the outer shell to absorb more energy, therefore generating a lower HIC which means a lower chance of critical and fatal injuries.

More efficient manufacturing could lead to cheaper, tougher helmets

The prototype helmet is also easier to produce than a conventional helmet. Using Elium® instead of other conventional thermoplastics simplifies the composite helmet manufacturing process.

Elium® is liquid at ambient temperature, allowing it to be moulded at room temperature as opposed to other thermoplastic-based composite shells that require higher temperature processing.

The NTU researchers are working with Arkema to commercialise the helmet's manufacturing process, which would allow interested manufacturers to produce them. Assoc Prof Leong says that helmets produced through their method would offer the same protection of current top-tier helmets, but potentially at the price of mid-tier helmets ($100-$150).

The researchers are currently working on developing composite helmets made from Elium® and polypropylene fabric, which is another type of thermoplastic. This is to overcome the composite helmet's one current trade-off which is that they weigh about 20 per cent more than polycarbonate helmets.

Helmets made from Elium® and polypropylene fabric will potentially make them just as light as polycarbonate ones but offer better protection.

Credit: 
Nanyang Technological University

3D imaging reveals neural 'vicious cycle' in fatty liver disease

image: Sympathetic nerves (white) around the portal vein (blue), the bile duct (yellow) and the hepatic artery (red) in the liver.

Image: 
Adori et al., Science Advances, July 2021.

With the application of a novel three-dimensional imaging technology, researchers at Karolinska Institutet in Sweden have discovered that one portion of the autonomic nervous system in the liver undergoes severe degeneration in non-alcoholic fatty liver disease. The study, which is conducted in mice and human liver tissue, shows that the degeneration of nerves is correlated with the severity of liver pathology. The results are being published in the journal Science Advances.

Non-alcoholic fatty liver disease is the most common hepatic disorder, with prevalence around 25 percent globally. Approximately one third of all fatty liver cases will develop to steatohepatitis, which is a severe disease seriously affecting the entire metabolism.

In the current paper, researchers explore the nervous system in fatty liver using volume immuno-imaging and light sheet microscopy ? a novel imaging technique, which altogether offer large-scale 3D visualization with cellular resolution. According to the study, this technology can reveal even early, minor or hidden structural impairments of the liver.

"Now we know that nerves in the liver have multiple subtle regulatory roles" says Csaba Adori, researcher at the Department of Neuroscience, who led the study. "Their role, however, may be more essential during the fight-or-flight response or when subjected to metabolic challenges. Degeneration of liver sympathetic nerves and abnormal operation of the remaining nerve fibres in the fatty liver could compromise all these functions, which may contribute to further aggravation of the disease, as part of a vicious cycle."

According to the study, alterations in the liver innervation occurs already in early stages of fatty liver disease. With progression to the more severe steatohepatitis, these impairments turn to a pronounced degeneration of the nerves. The nerve pathology is also similar in mouse model of fatty liver and in human fatty liver samples. The research team now hopes that the study results will open the door for new therapeutic approaches in the treatment of steatohepatitis and portal hypertension, by targeting the liver sympathetic nervous system.

Credit: 
Karolinska Institutet

Disagreement may be a way to make online content spread faster, further

ORLANDO, July 22, 2021 - Disagreement seems to spread online posts faster and further than agreement, according to a new study from the University of Central Florida.

The finding comes from an examination of posts labeled controversial on social news aggregation site Reddit. To perform the study, the researchers analyzed more than 47,000 posts about cybersecurity in a Reddit dataset that was collected by the Computational Simulation of Online Social Behavior (SocialSim) program of the U.S. Defense Advanced Research Projects Agency.

Researchers found that these posts were seen by nearly twice the number of people and traveled nearly twice as fast when compared to posts not labeled controversial. The findings were published recently in the Journal of Computational Social Science.

Reddit is one of the most visited websites in the U.S. A post is labeled controversial by a Reddit algorithm if it receives a certain number of polarized views, or a moderator can label a post with any number of comments as controversial.

The posts analyzed in the study included topics that wouldn't be considered traditionally controversial but were labeled as so by Reddit, such as a personal computer giveaway offer.

The research is important because it shows that disagreement may be a powerful way to get people to pay attention to messages, says study co-author Ivan Garibay, an associate professor in UCF's Department of Industrial Engineering and Management Systems.

However, he advises caution to those inducing disagreement in their social media posts.

"There may be an incentive in terms of influence and audience size for a social media user to consistently include controversial and provocative topics on their posts," Garibay says. "This benefits the person posting the messages. However, controversial comments can be divisive, which could contribute to a polarized audience and society."

Reddit's definition of a controversial post, which tends to depend on increasing numbers of both likes and dislikes, is different than the traditional advertiser's definition of a controversial post, which would contain truly provocative or taboo messaging, says Yael Zemack-Rugar, an associate professor in UCF's Department of Marketing.

"To give this idea life, you may like a recent ad for Toyota, and I may not," Zemack-Rugar says. "This will not make it controversial. But if the ad featured Colin Kaepernick, as the Nike ad did in 2018, after he recently refused to recite the national anthem during his games, now we are talking controversial. There is an underlying tone that is much deeper and more meaningful."

Reddit posts are also more akin to word-of-mouth communication since they are user generated and not paid advertising, she says.

The study's findings are consistent with past research that has found that traditional controversy increases the spread of word of mouth and discussions online, especially when contributions are anonymous, as they somewhat are on Reddit, Zemack-Rugar says.

Of the more than 47,000 posts, approximately 23,000 posts were labeled controversial, and about 24,000 were noncontroversial.

The researchers found an association between controversially labeled comments and the collective attention that the audience paid to them.

For the controversial posts, there were more than 60,000 total comments, whereas for the noncontroversial posts, there were less than 25,000 total comments.

A network analysis examining the reach and speed of the posts, showed that nearly twice the number of people saw controversial content compared to noncontroversial content and that controversial content traveled nearly twice as fast.

The researchers limited posts in their analysis to those that had at least 100 comments.

Jasser Jasser, a doctoral student in UCF's Department of Computer Science, and the study's lead author, says the findings highlight the need to better understand why the content labeled in Reddit as controversial spreads.

"The next step in this work is to analyze the language used to induce such controversy and why it brings the attention of the social media users," Jasser says.

Credit: 
University of Central Florida

Longitudinal serological and vaccination responses to SARS-COV-2 in dental professionals

Alexandria, Va., USA - Iain Chapple, University of Birmingham, England, presented the oral session "Longitudinal Serological and Vaccination Responses to SARS-COV-2 in Dental Professionals" at the virtual 99th General Session & Exhibition of the International Association for Dental Research (IADR), held in conjunction with the 50th Annual Meeting of the American Association for Dental Research (AADR) and the 45th Annual Meeting of the Canadian Association for Dental Research (CADR), on July 21-24, 2021.

The COVID-19 pandemic significantly impacted dental professionals, who are thought to be at high occupational risk of infection. The aim of this study was to determine the magnitude, persistence and neutralizing capacity of serum antibody responses to the SARS-COV-2 spike glycoprotein at baseline (3-months following first wave), 3- and 6-months in an observational cohort of United Kingdom dental professionals, and the IgG threshold for protection from re-infection.

Participants provided baseline venous blood samples and the total antibody response (combined IgG, A and M), and individual isotype response against the SARS-CoV-2 spike glycoprotein were measured. The neutralizing ability of antibodies was determined using a plaque reduction micro-neutralization assay.

Baseline seroprevalence was 16.3%. Seropositivity was retained in 73% of participants who returned 3-months post-baseline and 72% of participants who returned at 6-months, prior to their vaccination. Seropositivity arising following natural infection during the first wave, conferred a 74% risk reduction for re-infection during follow-up (9.6% seronegative, vs. 2.8% seropositive). The results show that natural infection with SARS-COV-2 leads to persistent, neutralizing and protective serological responses in over 70% of DPs 9-months post-infection (6-months post-baseline).

Credit: 
International Association for Dental, Oral, and Craniofacial Research

New study reports strong indications of freshened groundwater offshore the Maltese Islands

image: A map of the location of the freshened water.

Image: 
Prof. Aaron Micallef

An international team of scientists has reported strong indications of freshened groundwater offshore the coastline between Valletta and Marsascala, in the south-east of Malta.

This discovery is based on an oceanographic expedition carried out in 2018.

Seismic reflection profiles acquired during this expedition were used to generate a geological model of the seafloor offshore the Maltese Islands, whereas electromagnetic surveying was carried out to identify resistivity anomalies, or high values of electromagnetic resistivity beneath the seafloor.

These observations indicate that freshened groundwater occurs as an isolated body hosted in Globigerina Limestone located 3 km away from the coast.

Numerical modelling, on the other hand, suggests that a second offshore groundwater body may exist within 1 km of the Maltese coastline, and that the bulk of the groundwater was deposited 20,000 years ago when sea-level was lower than today.

There are a number of important implications associated with this discovery.

Offshore freshened groundwater may constitute a new, unconventional source of potable water that should be considered in future national water management strategies for the Maltese Islands.

The occurrence of freshened groundwater offshore a dry, limestone coastline such as the Maltese one bodes well for similar settings in the Mediterranean region that are suffering from water scarcity. On the other hand, the exploitation of the Maltese offshore groundwater system is likely unsustainable, because it is not being actively recharged, and pumping rates are likely to be low.

The study, which is a product of the MARCAN project, has now been published in the international journal Geophysical Research Letters and may be read online.

The team involved in this study includes scientists from Malta, Germany, Spain and Italy.

Credit: 
University of Malta