Culture

In a groundbreaking new study, researchers at the University of Minnesota, in collaboration with the U.S. Army Combat Capabilities Development Command Soldier Center, have 3D printed unique fluid channels at the micron scale that could automate production of diagnostics, sensors, and assays used for a variety of medical tests and other applications.

The team is the first to 3D print these structures on a curved surface, providing the initial step for someday printing them directly on the skin for real-time sensing of bodily fluids. The research is published in Science Advances, a peer-reviewed scientific journal published by the American Association for the Advancement of Science (AAAS).

Microfluidics is a rapidly growing field involving the control of fluid flows at the micron scale (one millionth of a meter). Microfluidics are used in a wide range of application areas including environmental sensing, medical diagnostics (such as COVID-19 and cancer), pregnancy testing, drug screening and delivery, and other biological assays.

The global microfluidics market value is currently estimated in the billions of dollars. Microfluidic devices are typically fabricated in a controlled-environment cleanroom using a complex, multi-step technique called photolithography. The fabrication process involves a silicone liquid that is flowed over a patterned surface and then cured so that the patterns form channels in the solidified silicone slab.

In this new study, the microfluidic channels are created in a single step using 3D printing. The team used a custom-built 3D printer to directly print the microfluidic channels on a surface in an open lab environment. The channels are about 300 microns in diameter--about three times the size of a human hair (one one-hundredth of an inch). The team showed that the fluid flow through the channels could be controlled, pumped, and re-directed using a series of valves.

Printing these microfluidic channels outside of a cleanroom setting could provide for robotic-based automation and portability in producing these devices. For the first time, the researchers were also able to print microfluidics directly onto a curved surface. In addition, they integrated them with electronic sensors for lab-on-a-chip sensing capabilities.

"This new effort opens up numerous future possibilities for microfluidic devices," said Michael McAlpine, a University of Minnesota mechanical engineering professor and senior researcher on the study. "Being able to 3D print these devices without a cleanroom means that diagnostic tools could be printed by a doctor right in their office or printed remotely by soldiers in the field."

But McAlpine said the future is even more compelling.

"Being able to print on a curved surface also opens up many new possibilities and uses for the devices, including printing microfluidics directly on the skin for real-time sensing of bodily fluids and functions," said McAlpine, who holds the Kuhrmeyer Family Chair Professorship in the Department of Mechanical Engineering.

A research team at LKS Faculty of Medicine, The University of Hong Kong (HKUMed) discovered that exosomes derived from Vδ2-T cells (Vδ2-T-Exos) can effectively control Epstein-Barr virus-associated tumours and induce T-cell anti-tumour immunity. The novel findings of Vδ2-T-Exos provide insights into new therapeutic approach for Epstein-Barr virus (EBV)-associated tumours. The ground-breaking findings have been published in the leading academic journal, Science Translational Medicine. [Link to the publication]

Background

EBV infects about 95% of the human population and causes more than 200,000 cases of cancer each year and that around 2% of all cancer deaths are due to EBV-attributable malignancies. EBV-associated tumours include Burkitt lymphoma, Hodgkin lymphoma, nasopharyngeal carcinoma, gastric tumour and post-transplant lymphoproliferative disease, etc. Current treatment options for EBV-associated tumours are limited with considerably unwanted off-target toxicities and incomplete effectiveness for relapsed or refractory disease. Vδ2-T cells are innate-like T cells with anti-tumour potentials against EBV-associated tumours. Unfortunately, its clinical translation is limited because Vδ2-T cells from some cancer patients are difficult to be expanded. Exosomes are endosome-originated small extracellular vesicles that mediate intercellular communication. Compared with cell-based therapy, cell-free exosomes have advantages with higher safety, easier storage, and lower costs. However, the anti-tumour activity of exosomes derived from Vδ2-T cells (Vδ2-T-Exos) remains unknown.

Research findings

Herein, the team found that Vδ2-T-Exos contained death-inducing ligands (FasL and TRAIL) and immunostimulatory molecules (CD80, CD86, MHC class I and II). Vδ2-T-Exos targeted and efficiently killed EBV-associated tumour cells through FasL and TRAIL pathways and promoted EBV antigen-specific CD4 and CD8 T cell expansion. Administration of Vδ2-T-Exos effectively controlled EBV-associated tumours in immunodeficient and humanized mice. Because expanding Vδ2-T cells and preparing autologous Vδ2-T-Exos from cancer patients ex vivo in large scale is challenging, the team further explored the anti-tumour activity of allogeneic Vδ2-T-Exos in humanized mouse cancer models. Interestingly, the team found that allogeneic Vδ2-T-Exos had more effective anti-tumour activity than autologous Vδ2-T-Exos in humanized mice; the allogeneic Vδ2-T-Exos increased the infiltration of T cells into tumour tissues and induced more robust CD4 and CD8 T cells-mediated anti-tumour immunity. Compared with exosomes derived from NK cells with direct cytotoxic anti-tumour activity or dendritic cells that induced T-cell anti-tumour responses, Vδ2-T-Exos have dual anti-tumour activities by directly killing tumour cells and indirectly inducing T cells-mediated anti-tumour responses, thus resulting in more effective control of EBV-associated tumours.

"Our study provides the first evidence about the anti-tumour activities of Vδ2-T-Exos against EBV-associated tumours. These exosomes could effectively control EBV-associated cancers in multiple mouse models. More importantly, allogeneic Vδ2-T-Exos had higher therapeutic efficacy than autologous Vδ2-T-Exos to control EBV-associated tumours. Therefore, the Vδ2-T-Exos prepared from healthy donors can be used to treat patients with EBV-associated tumours, which is highly beneficial to the clinical application of this novel approach," said Professor Tu Wen-wei, Antony and Nina Chan professor in Paediatric Immunology, Department of Paediatrics and Adolescent Medicine, HKUMed, who led the research.

Significance of the study

The findings of the study have significant implications in cancer immunotherapy. Firstly, the identification that Vδ2-T-Exos has potent immunostimulatory property suggests that they could be designed as a cancer vaccine by serving as immune adjuvant and delivering immunogens. Secondly, the Vδ2-T-Exos has advantages over other exosome-based therapies (e.g. NK-Exos and DC-Exos) by displaying dual anti-tumour activities and are easier in preparation. Thirdly, the results that allogeneic Vδ2-T-Exos have higher anti-tumour efficacies than autologous Vδ2-T-Exos can greatly enhance the clinical feasibility of Vδ2-T-Exos, because the preparation of allogeneic exosomes does not require personalized procedures and is easier in quality control, standardization and centralization for clinical application.

A research collaboration between Queen Mary University of London, the University of Cambridge and the Institute for High Pressure Physics in Troitsk has discovered the fastest possible speed of sound.

The result- about 36 km per second - is around twice as fast as the speed of sound in diamond, the hardest known material in the world.

Waves, such as sound or light waves, are disturbances that move energy from one place to another. Sound waves can travel through different mediums, such as air or water, and move at different speeds depending on what they're travelling through. For example, they move through solids much faster than they would through liquids or gases, which is why you're able to hear an approaching train much faster if you listen to the sound propagating in the rail track rather than through the air.

Einstein's theory of special relativity sets the absolute speed limit at which a wave can travel which is the speed of light, and is equal to about 300,000 km per second. However until now it was not known whether sound waves also have an upper speed limit when travelling through solids or liquids.

The study, published in the journal Science Advances, shows that predicting the upper limit of the speed of sound is dependent on two dimensionless fundamental constants: the fine structure constant and the proton-to-electron mass ratio.

These two numbers are already known to play an important role in understanding our Universe. Their finely-tuned values govern nuclear reactions such as proton decay and nuclear synthesis in stars and the balance between the two numbers provides a narrow 'habitable zone' where stars and planets can form and life-supporting molecular structures can emerge. However, the new findings suggest that these two fundamental constants can also influence other scientific fields, such as materials science and condensed matter physics, by setting limits to specific material properties such as the speed of sound.

The scientists tested their theoretical prediction on a wide range of materials and addressed one specific prediction of their theory that the speed of sound should decrease with the mass of the atom. This prediction implies that the sound is the fastest in solid atomic hydrogen. However, hydrogen is an atomic solid at very high pressure above 1 million atmospheres only, pressure comparable to those in the core of gas giants like Jupiter. At those pressures, hydrogen becomes a fascinating metallic solid conducting electricity just like copper and is predicted to be a room temperature superconductor. Therefore, researchers performed state-of-the-art quantum mechanical calculations to test this prediction and found that the speed of sound in solid atomic hydrogen is close to the theoretical fundamental limit.

Professor Chris Pickard, Professor of Materials Science at the University of Cambridge, said: "Soundwaves in solids are already hugely important across many scientific fields. For example, seismologists use sound waves initiated by earthquakes deep in the Earth interior to understand the nature of seismic events and the properties of Earth composition. They're also of interest to materials scientists because sound waves are related to important elastic properties including the ability to resist stress."

Seismic waves, commonly associated with earthquakes, have been used by scientists to develop a universal scaling law for the sense of touch. A team, led by researchers at the University of Birmingham, used Rayleigh waves to create the first scaling law for touch sensitivity. The results are published in Science Advances.

The researchers are part of a European consortium (H-Reality) that are already using the theory to develop new Virtual Reality technologies that incorporate the sense of touch.

Rayleigh waves are created by impact between objects and are commonly thought to travel only along surfaces. The team discovered that, when it comes to touch, the waves also travel through layers of skin and bone and are picked up by the body's touch receptor cells.

Using mathematical modelling of these touch receptors the researchers showed how the receptors were located at depths that allowed them to respond to Rayleigh waves. The interaction of these receptors with the Rayleigh waves will vary across species, but the ratio of receptor depth vs wavelength remains the same, enabling the universal law to be defined.

The mathematics used by the researchers to develop the law is based on approaches first developed over a hundred years ago to model earthquakes. The law supports predictions made by the Nobel-Prize-winning physicist Georg von Békésy who first suggested the mathematics of earthquakes could be used to explore connections between Rayleigh waves and touch.

The team also found that the interaction of the waves and receptors remained even when the stiffness of the outermost layer of skin changed. The ability of the receptors to respond to Rayleigh waves remained unchanged despite the many variations in this outer layer caused by, age, gender, profession, or even hydration.

Dr Tom Montenegro-Johnson, of the University of Birmingham's School of Mathematics, led the research. He explains: "Touch is a primordial sense, as important to our ancient ancestors as it is to modern day mammals, but it's also one of the most complex and therefore least understood. While we have universal laws to explain sight and hearing, for example, this is the first time that we've been able to explain touch in this way."

James Andrews, co-author of the study at the University of Birmingham, adds: "The principles we've defined enable us to better understand the different experiences of touch among a wide range of species. For example, if you indent the skin of a rhinoceros by 5mm, they would have the same sensation as a human with a similar indentation - it's just that the forces required to produce the indentation would be different. This makes a lot of sense in evolutionary terms, since it's connected to relative danger and potential damage."

By applying natural language processing tools to the movements of protein molecules, University of Maryland scientists created an abstract language that describes the multiple shapes a protein molecule can take and how and when it transitions from one shape to another.

A protein molecule's function is often determined by its shape and structure, so understanding the dynamics that control shape and structure can open a door to understanding everything from how a protein works to the causes of disease and the best way to design targeted drug therapies. This is the first time a machine learning algorithm has been applied to biomolecular dynamics in this way, and the method's success provides insights that can also help advance artificial intelligence (AI). A research paper on this work was published on October 9, 2020, in the journal Nature Communications.

"Here we show the same AI architectures used to complete sentences when writing emails can be used to uncover a language spoken by the molecules of life," said the paper's senior author, Pratyush Tiwary, an assistant professor in UMD's Department of Chemistry and Biochemistry and Institute for Physical Science and Technology. "We show that the movement of these molecules can be mapped into an abstract language, and that AI techniques can be used to generate biologically truthful stories out of the resulting abstract words."

Biological molecules are constantly in motion, jiggling around in their environment. Their shape is determined by how they are folded and twisted. They may remain in a given shape for seconds or days before suddenly springing open and refolding into a different shape or structure. The transition from one shape to another occurs much like the stretching of a tangled coil that opens in stages. As different parts of the coil release and unfold, the molecule assumes different intermediary conformations.

But the transition from one form to another occurs in picoseconds (trillionths of a second) or faster, which makes it difficult for experimental methods such as high-powered microscopes and spectroscopy to capture exactly how the unfolding happens, what parameters affect the unfolding and what different shapes are possible. The answers to those questions form the biological story that Tiwary's new method can reveal.

Tiwary and his team applied Newton's laws of motion--which can predict the movement of atoms within a molecule--with powerful supercomputers, including UMD's Deepthought2, to develop statistical physics models that simulate the shape, movement and trajectory of individual molecules.

Then they fed those models into a machine learning algorithm, like the one Gmail uses to automatically complete sentences as you type. The algorithm approached the simulations as a language in which each molecular movement forms a letter that can be strung together with other movements to make words and sentences. By learning the rules of syntax and grammar that determine which shapes and movements follow one another and which don't, the algorithm predicts how the protein untangles as it changes shape and the variety of forms it takes along the way.

To demonstrate that their method works, the team applied it to a small biomolecule called riboswitch, which had been previously analyzed using spectroscopy. The results, which revealed the various forms the riboswitch could take as it was stretched, matched the results of the spectroscopy studies.

"One of the most important uses of this, I hope, is to develop drugs that are very targeted," Tiwary said. "You want to have potent drugs that bind very strongly, but only to the thing that you want them to bind to. We can achieve that if we can understand the different forms that a given biomolecule of interest can take, because we can make drugs that bind only to one of those specific forms at the appropriate time and only for as long as we want."

An equally important part of this research is the knowledge gained about the language processing system Tiwary and his team used, which is generally called a recurrent neural network, and in this specific instance a long short-term memory network. The researchers analyzed the mathematics underpinning the network as it learned the language of molecular motion. They found that the network used a kind of logic that was similar to an important concept from statistical physics called path entropy. Understanding this opens opportunities for improving recurrent neural networks in the future.

"It is natural to ask if there are governing physical principles making AI tools successful," Tiwary said. "Here we discover that, indeed, it is because the AI is learning path entropy. Now that we know this, it opens up more knobs and gears we can tune to do better AI for biology and perhaps, ambitiously, even improve AI itself. Anytime you understand a complex system such as AI, it becomes less of a black-box and gives you new tools for using it more effectively and reliably."

Bottom Line: Analysis of DNA copy number variants (CNVs) in the cells exfoliated in urine showed better sensitivity and similar specificity in detecting urothelial carcinoma compared with urine cytology.

Journal in Which the Study was Published:
Clinical Cancer Research, a journal of the American Association for Cancer Research

Authors: Chuan-Liang Xu, MD, PhD, urologist at Changhai Hospital in Shanghai; and Jia-Tao Ji, MD, PhD, urologist at Shanghai Hudong Hospital

Background: "Urine cytology, which is widely used to screen for bladder cancer, has high specificity but lacks sensitivity, especially for low-grade cancers," said Xu. "Cystoscopy, while more accurate than cytology, is an invasive procedure with added costs and potential complications for the patient," he added. "Therefore, an inexpensive, non-invasive test for the detection and monitoring of bladder cancer is an unmet clinical need."

"The DNA isolated from urine exfoliated cells, a complex cell mixture that potentially includes tumor cells shed from the lining of the bladder, can provide clues to the presence of bladder cancer," said Ji. "Because CNVs are a hallmark of many cancers, we developed an assay to detect CNV burden in the DNA from urine exfoliated cells."

How the Study was Conducted & Results: The assay, called UroCAD, begins with a urine sample. Following urine sedimentation and DNA extraction, the sample is analyzed using low-coverage whole-genome sequencing (LC-WGS). Because the assay relies on the detection of overall CNV burden, and not on the identification of specific genetic alterations, this cost-effective sequencing method is an ideal technique for sample analysis, noted Xu.

The researchers used samples from patients enrolled in an observational clinical trial in Shanghai that is evaluating the UroCAD assay. A total of 190 patients (126 with urothelial carcinoma, 64 without cancer) participated in the discovery phase; no significant CNV burden was detected in those without cancer. The researchers then developed a diagnostic model which incorporated all autosomal chromosomal changes in urine exfoliated cells. In the discovery cohort, UroCAD identified urothelial carcinoma with a sensitivity and specificity of 82.5 percent and 96.9 percent, respectively.

The UroCAD assay was then evaluated in a validation cohort comprising 95 patients (56 with urothelial carcinoma, 39 without cancer). When compared with urine cytology, the researchers found that UroCAD had significantly higher sensitivity (80.4 percent versus 33.9 percent) and comparable specificity (94.9 percent versus 100 percent) for the detection of urothelial carcinoma. Further, in the seven patients whose low-grade tumors were confined to the epithelial layer of the bladder (pTa tumors), UroCAD had a sensitivity of 71.4 percent, while urine cytology had a sensitivity of 0 percent.

The sensitivity of UroCAD corresponded with tumor grade, as it could detect low-grade and high-grade urothelial carcinoma with a sensitivity of 60 percent and 86.6 percent, respectively. Further, the sensitivity of the test correlated with tumor size; the sensitivity of detection for tumors of 1 cm or less, tumors between 1 and 3 cm, and tumors greater than 3 cm was 66.7 percent, 72 percent, and 95.5 percent, respectively.

Authors' Comments: "The relatively lower sensitivity of UroCAD for the detection of lower grade or smaller tumors is not unexpected, as these tumors are less likely to have abundant chromosomal alterations," said Xu. "Ultimately, we believe that our assay could help to reduce the frequency of cystoscopy examination, but not to replace it."

"For patients with hematuria or who have suspected urothelial carcinoma, UroCAD is a promising way to replace cytology and to reduce repeated cystoscopy examinations," Ji said. The use of UroCAD for the surveillance of urothelial carcinoma is currently being evaluated in a clinical trial.

Study Limitations: The detection of CNV burden was correlated with the amount of epithelial cells present, suggesting that a lack of sufficient exfoliated cells may limit the assay, Xu noted.

The COVID-19 pandemic provides an opportunity to reset the global economy and reverse decades of ecosystem and species losses, but most countries are failing to invest in nature-related economic reforms or investments, according to a Rutgers-led paper.

Indeed, some countries, including the United States, Brazil and Australia, are back-tracking on existing laws and relaxing regulations and enforcement actions aimed at protecting nature, according to lead author Pamela McElwee, an associate professor in the Department of Human Ecology in the School of Environmental and Biological Sciences at Rutgers University-New Brunswick.

"Just last week at the United Nations, more than 60 heads of state spoke at a virtual summit and pledged their support to tackle the biodiversity crisis. But when we look at what countries are doing, either in their prior budget and policies or especially in their post-COVID planning and recovery packages, very few governments are putting their money where their mouths are," McElwee said. "We still see huge amounts of financial support for harmful practices, such as subsidizing overfishing or fossil fuel production or building infrastructure that will harm ecological integrity. Only a small number of countries are addressing the biodiversity crisis in the serious manner it deserves."

The paper, by economists, anthropologists and environmental scientists at many institutions on three continents, is published in the journal One Earth. It explores the changes in global economic systems - including incentives, regulations, fiscal policy and employment programs - that are necessary to shift away from activities that damage biodiversity and move toward those supporting ecosystem resilience.

Unless action is taken, around 1 million species face extinction, many within decades, and the global rate of species extinction will accelerate, according to the 2019 Global Assessment Report on Biodiversity and Ecosystem Services from the Intergovernmental Science-Policy Platform on Biodiversity and Ecosystem Services (IPBES). That report noted the extinction rate is "already at least tens to hundreds of times higher than it has averaged over the past 10 million years." The authors of this new paper were all contributors to the 2019 IPBES report.

The new paper spells out the actions governments should be taking in their stimulus and recovery plans that would prioritize nature, provide immediate employment benefits and lead to longer-term transformations in the global economy. Examples include shifting from harmful fossil fuel subsidies to beneficial ones, including those that encourage environmentally friendly farming; carbon taxes that could support forest protection programs; and work programs that focus on ecological restoration and green infrastructure.

While many scientists and politicians have promoted a COVID-19 recovery that is low carbon, how to include biodiversity and ecosystems in economic plans has received much less attention. Discussions of nature-related actions have largely focused on closing wildlife markets as a potential source of novel viruses, expanding protected natural areas or reducing tropical deforestation. While these can be important, they do not necessarily address the root causes of ecological disruptions, the authors say.

A number of countries, including the United States and China, have allocated essentially zero stimulus funding to biodiversity or ecosystems. Only the European Union and member countries are making substantial financial investments in biodiversity for post-COVID planning. Other nations, including New Zealand, India and Pakistan, are proposing investments in nature-based jobs like ecological restoration, but at only modest levels.

"Governments are falling short of their stated promises and they need to do more - immediately," McElwee said. "We will continue to monitor proposed recovery packages, stimulus measures and financial pledges for how they address the biodiversity crises going forward, particularly in light of the mega-summit on biodiversity to be held in China next May."

Could something as simple as a certain type of sugar water be medicine for perforated bones, and even bone marrow cancer itself?

Inside our bodies are some jellyfish-like cells that actually eat away at our bones. Every year, they eat about ten per cent of the bone mass in our body. Fortunately, other cells usually follow and build up new bone.

We undergo a kind of continuous remodelling and repair that enables most of us to traipse around with steel in our legs and arms.

In people with bone marrow cancer, the bone-eating cells run amok. They become too numerous and eat too much. The bone-building gang doesn't have time to rebuild the bone mass, despite overtime and long shifts. Bone tissue gets gobbled up.

Many people with bone marrow cancer often end up with perforated bones, a condition that is very painful to live with. They sometimes experience collapsed vertebrae or suffer broken bones just by turning in bed.

For decades, scientists around the world have been scratching their heads and wondering what the cause could be. Various theories have been launched, but researchers have not reached a consensus on the main cause.

Bone marrow cancer remains an incurable disease so far. Available treatments can prolong life, but not cure the disease.

Now Standal and her research group at the Centre of Molecular Inflammation Research (CEMIR) at the Norwegian University of Science and Technology (NTNU) have discovered a piece of the puzzle that looks very promising.

They have come to the conclusion that the cause of the bone destruction is too little sugar. We're not talking about the sugar we eat in our cakes and biscuits, but sugar that resides in a substance that is important for the immune system.

To get to the bottom of how sugar is related to bone loss, we need to get into the bone marrow. This is the soft cavity that inside all our bones.

Within the bones are plasma cells. When bacteria or viruses enter the body, the plasma cells begin their job of getting rid of the invaders. Antibodies are produced which are sent via the blood, ready to do battle.

So far so good, but in people with bone marrow cancer, far too much of one type of antibody is produced. It's going amok here, too. The antibody that the cancer makes is also completely useless. It doesn't knock out either the cold or the flu but just takes up too much space and displaces other types of antibodies.

"I thought simply. If people with bone marrow cancer have too much of the antibody and too many bone-eating cells, then they must be connected," Standal says.

The search for an answer gobbled a lot of her working hours for almost five years. The hard work was fortunately not in vain, and has led to a completely new and fundamental understanding.

The finding has now been published in Blood, the highest ranked blood disease journal in in the world.

This is how Standal arrived at the answer:

The vast majority of patients with bone marrow cancer develop perforated bones, but not all. Standal asked nicely, and received samples from patients with bone loss. She also took samples from patients without this kind of bone loss.

The researchers extracted antibodies from the samples and cultured bone-eating cells in the laboratory.

When Standal placed the bone-eating cells into the antibody of the patients with bone perforations, she discovered that the number of bone-eating cells increased.

When she put the bone-eating cells into the antibody of the patients without bone perforations, she discovered that the number of bone-eating cells did not increase.

"Why that was the case became the next interesting thing to figure out," Standal says.

The antibody carries a type of sugar that "decorates" it, in a way. The sugar has an effect on how the antibody works. Standal found her way to Manfred Wuhrer at the Center for Proteomics and Metabolomics of the Leiden University Medical Center in the Netherlands. He is a specialist in this type of sugar, and Standal sent the samples to him.

He found that individuals with bone loss were missing two sugar molecules at the end of a long chain inside the antibody.

"There was too little sugar," says Standal.

But this answer wasn't sufficient, either.

Although a difference was detected between the two groups, the researchers could not confirm that the missing sugar molecules were the reason patients developed more bone-eating cells. Several further experiments had to be conducted.

The research team went to the lab and put more sugar on the antibody. This did not lead to more bone-eating cells. Standal also did the opposite, removing sugar from the antibody. This did lead to more bone-eating cells.

The researchers then had sufficient test results to show that too little sugar can be decisive for the number of bone-eating cells. But this is not enough in medical research - at least not if the goal is to use the knowledge to make medicine for humans.

The next step involved animal experiments with mice that have bone marrow cancer. The mice were divided into two groups and were given two different types of sugar water. In theory, one type of sugar water would lead to more sugar on the antibody.

"The theory actually worked. The mice that received this type of sugar water had smaller perforations in their bone tissue. They also developed less cancer," says Standal.

Now she has to carry out more animal experiments to move forward on the path towards a treatment that can give patients with bone marrow cancer a better life.

"I think it might be realistic to try this on a small group of patients in four to five years," says Standal.

Leesburg, VA, October 9, 2020--According to an article in ARRS' American Journal of Roentgenology (AJR), the imaging findings of in situ pulmonary artery thrombosis (PAT) associated with radiation therapy (RT) are different from those of acute pulmonary emboli and do not appear to embolize. Due to the differences in clinical prognosis and subsequent management strategies, in situ PAT associated with RT--"which to our knowledge has not previously been described in the English literature," wrote the authors of this AJR article--must be distinguished from pulmonary embolism.

Searching the radiology database of a large teaching hospital to identify patients who had PAT develop after receiving RT, first author Jitesh Ahuja from the thoracic imaging department at the University of Texas' MD Anderson Cancer Center recorded the PAT's CT characteristics: number, location, appearance of filling defects, as well as the presence of associated lung fibrosis. The terminology (in situ thrombosis vs acute or chronic pulmonary embolism) used to describe PAT, the time between completion of RT and development of PAT, the size change of PAT, and any observation of new thrombi and emboli on follow-up imaging were also recorded.

With a study population consisting of 27 patients (19 men and eight women) at a mean age of 71 (range, 54-90 years), the primary malignancy was lung cancer in 22 patients (81%) and mesothelioma in five patients (19%). Whereas most PATs were solitary (93%) and nonocclusive (96%) and formed an obtuse angle to the vessel wall (89%), all PATs were eccentric within the involved pulmonary artery and located within the RT volume. The time from completion of RT to initial diagnosis of PAT on CT ranged from 53 to 2,522 days (mean, 675 days). In all patients, CT findings of radiation-induced lung fibrosis were present in the lung supplied by the affected pulmonary artery. "On follow-up imaging, none of the patients were observed to have filling defects develop in other parts of the PA, which would have suggested embolization," Ahuja et al. added.

Acknowledging that RT is a "key choice" in multimodality treatment of intrathoracic malignancies, the authors noted that RT-associated cardiovascular complications remain the leading non-cancer-related cause of morbidity and mortality among cancer survivors. "Radiologist awareness of PAT can facilitate accurate diagnosis and impact management," they concluded.

A team of chemists from RUDN University suggested a new reaction to produce organic compounds in one vessel. The end products turned out to be effective against the cells of carcinomas, including drug-resistant ones. The new reaction was described in the Bioorganic Chemistry journal.

For many organic substances synthesis is a multistage process of step-by-step molecule assembly. At each stage, only one chemical bond is formed. After each step, the product is purified and used in the next reaction. Domino reactions are a cascade of reactions that happen one after another in one vessel without any additional reagents. A team of chemists from RUDN University in collaboration with University of Bari, identified a number of substances that initiate a domino synthesis of chromenoisoquinolineamine derivatives. Similar compounds are used as anti-inflammatory and antitumor drugs, and some of them can potentially treat Alzheimer's disease.

The team suggested using salicylaldehyde (a derivative of salicylic acid) and homophthalonitrile and catalyzing the reaction with ammonium formate that is cheap and eco-friendly. The initial reagents were mixed with water and isopropyl alcohol and put into a microwave reactor where the mixture was heated up to 150°C for 20 minutes. The researchers used salicylaldehydes with different substituents and as a result, received 19 derivatives of chromenoisoquinolineamines with 43-85% yields of respective reaction products.

To analyze the medical potential of the new substances, the chemists tested their effect on human cancerous cells. Cisplatin that is used in chemotherapy and is known to kill tumor cells was taken as a benchmark for comparison. The team chose the cells of breast and colon cancers, as well as three strains of ovary cancer cells (two of which were cisplatin-resistant) for the test. All new substances turned out to be toxic for tumor cells, including the resistant strains. The researchers selected two compounds that proved to be efficient even in low concentrations and ran computer modeling. According to it, the reason for their efficiency was an additional amine group that forms a stable bond with the nucleotides of the cancer cells DNA.

"In our work, we searched for new compounds with promising therapeutic properties, as well as for ways to synthesize them. Our approach allows for the synthesis of tumor-combating substances in the course of one domino reaction that is extremely efficient: four new bonds are created within one synthetic operation. We worked together with our Italian partners, and the study was supported by the Russian Science Foundation. In the future, we plan to improve our methodology and develop three- and four-component reactions on its basis," said Alexey Festa, a Candidate of Chemical Sciences, and a senior lecturer at the Department of Organic Chemistry, RUDN University.

Banyan trees are fig trees that begin their life as an epiphyte. The most noticeable feature of banyan Ficus species is their extraordinary aerial roots, which enable them to live as hemi-epiphytes, as do the strangler figs often seen in tropical forests.

Being special for their enclosed urn-shaped inflorescence, fig plants rely on specific insect pollinators (fig wasps) for pollination and, in turn, provide nourishment and shelter for pollinators to reproduce. Morphological matching and signaling communication for host location between figs and their pollinators is required for successful pollination and oviposition.

This obligate mutualism is a fascinating case of extreme plant-insect codiversification.

In a study published in the journal Cell, researchers from Fujian Agriculture and Forestry University (FAFU) and the Xishuangbanna Tropical Botanical Garden (XTBG) provided insights into fig-wasp coevolution through comparative analyses of two Ficus genomes - one with aerial roots and one without, one monecious and one dioecious, as well as the genome of a coevolving wasp pollinator. They also sequenced more samples of figs and pollinators.

The researchers sequenced genomes of the monecious Chinese banyan tree, F. microcarpa, and a dioecious species lacking aerial roots, F. hispida, and one wasp genome coevolving with F. microcarpa, Eupristina verticillata. Comparative analysis of the two Ficus genomes revealed dynamic karyotype variation associated with adaptive evolution.

"We quantified endogenous auxin in F. microcarpa and F. hispida, and proposed that an auxin-dependent pathway promoted by light is associated with aerial root initiation, growth, and pattern formation," said WANG Gang, associate professor at XTBG and co-first author of the study.

Furthermore, the researchers constructed an ultra-density F1 paternal genetic map and Hi-C chromosome for studying sex determination and sex evolution in Ficus plants. They found a nascent Y chromosome in F. hispida and a male-specific AGAMOUS paralog, the FhAG2 gene, as a candidate sex determination gene of this fig species.

"We also established a phylogeny of Ficus by using data from resequenced genomes of 112 Ficus accessions comprising 62 Ficus species. Our phylogenetic analysis revealed that monoecy represents the ancestral reproductive system across the genus," noted the study.

Lastly, the researchers investigated a potential molecular mechanism of coevolution between 14 fig species of the subgenus Sycomorus and their obligate pollinator wasps. They identified candidate genes that had undergone selection, and the species-specific signaling compounds that were essential for communication in three fig-wasp species pairs.

"Population genomic analysis of subgenus Sycomorus figs and their obligate pollinator wasps and electrophysiological testing of pollinators responding to floral scents emitted from three different Ficus species support the important roles of the mevalonate and shikimate pathways in attracting species-specific pollinators and reveal potential molecular mechanisms of codiversification in this obligate mutualism," said WANG.

"The work, integrating efforts from several universities and institutes from China and overseas, particularly the expertise on genomic analysis from FAFU and fig biology from XTBG, will enhance our understanding of the species-specific mutualism between figs and fig wasps," said CHEN Jin, one of the corresponding authors of the study.

As of October 2020, SARS-CoV-2 causes an ongoing pandemic, with more than 35 million reported cases and more than 1 million deaths worldwide. One prominent feature that distinguishes COVID-19 from SARS in terms of immune responses is the poor induction of a type I interferon (IFN) response by SARS-CoV-2 compared to SARS-CoV and influenza A virus. Notably, impaired IFN responses are associated with COVID-19 disease. However, the molecular mechanisms underlying the inefficient IFN responses in SARS-CoV-2 infection remain unclear.

A research team at The Institute of Medical Science, The University of Tokyo (IMSUT) aimed to characterize the viral factor(s) determining immune activation upon SARS-CoV-2 infection and found that ORF3b, a gene encoded by SARS-CoV-2, is a potent IFN antagonist.

"The poor IFN responses in COVID-19 patients may be explained by the action of this viral product, ORF3b", said the lead scientist, Kei Sato, Associate Professor (Principal Investigator) at Division of Systems Virology, Department of Infectious Disease Control, IMSUT.

The results of this research were published in "Cell Reports" on September 4, 2020.

ORF3b as a viral IFN antagonist

Although SARS-CoV infection causes acute and severe pneumonia, SARS-CoV-2 infection may be asymptomatic or result in flu-like symptoms such as fever, cough and fatigue. Also, compared to SARS-CoV and influenza A virus infections, a hallmark of SARS-CoV-2 infection, COVID-19, is the poor induction of a type I interferon (IFN). Notably, impaired IFN responses are associated with the severity of COVID-19. However, the molecular mechanisms underlying the inefficient IFN responses in SARS-CoV-2 infection remain unclear.

By comparing the sequences of SARS-CoV-2-encoding genes to those of SARS-CoV, the research group found that the gene length of SARS-CoV-2 ORF3b is markedly shorter than that of SARS-CoV ORF3b.

Because ORF3b of SARS-CoV is known as a viral antagonist against IFN production, they hypothesized that the difference on the length of ORF3b gene between SARS-CoV-2 and SARS-CoV may alter their anti-IFN activity and further may explain the difference in the symptoms of these two viral infections.

Surprisingly, SARS-CoV-2 ORF3b is a more potent IFN antagonist than SARS-CoV ORF3b. Phylogenetic analyses and functional assays revealed that SARS-CoV-2-related viruses from bats and pangolins also encode shorter ORF3b gene products with strong anti-IFN activity.

Characterization of a natural SARS-CoV-2 ORF3b variant with enhanced anti-IFN activity

Furthermore, analyses of approximately 17,000 SARS-CoV-2 sequences identified a natural variant, in which a longer ORF3b reading frame was reconstituted. This variant suppresses IFN even more efficiently than ORF3b of the parental SARS-CoV-2 strain.

In agreement with an association of IFN suppression with disease severity, the two patients in Ecuador harboring SARS-CoV-2 with the extended ORF3b variant were critically ill; one was treated in an intensive care unit and the other one died of COVID-19.

Importantly, however, there is no direct evidence indicating that the viruses detected in these two COVID-19 patients in Ecuador are more pathogenic than the reference strain. Although they cannot tell whether this variant is associated with a different outcome in disease, it is plausible that naturally occurring length variants of ORF3b can potentially contribute to the emergence of more pathogenic SARS-CoV-2 variants.

Thus, it will be important to continue monitoring viral sequences to see whether novel ORF3b variants emerge during the current pandemic.

Associate Professor Kei Sato said that "To our knowledge, this study is the first investigation revealing the role of a SARS-CoV-2-encoded protein that can be associated with the progression of COVID-19".

Being a man, having a lower income, having a lower level of education, not being married, and being born abroad in low- or middle-income countries - these are factors that, independent of one another, are related to an elevated risk of dying from COVID-19 in Sweden. These are the findings of a new study in the journal Nature Communications from Stockholm University.

"We can show that there are independent effects of various separate risk factors that have been brought up in debates and news about COVID-19. All of these factors are accordingly individually associated with a strongly elevated risk of dying from COVID-19," said Sven Drefahl, Associate Professor of Demography at Stockholm University Demography Unit in the Department of Sociology, and main-author of the study.

When it comes to the elevated risk for people from low- and middle-income countries in, for example, the Middle East and North Africa of dying from COVID-19, it does not agree with the general patterns of mortality for that group. Sven Drefahl explains that those born abroad generally have a lower mortality than people born in Sweden. This also applies when the research took income and level of education into account. The elevated risk of dying from COVID-19 for this group remains after the researchers controlled for circumstances, such as income and level of education. The study also shows that the risk of dying from COVID-19 was much higher in the Stockholm area than outside, both for those born in Sweden and those born abroad, which can be explained by the spread of disease being greater in that area.

The study shows that being a man, having a lower income and lower level of education also result in a strongly elevated risk of dying from COVID-19. As to these aspects, this also agrees with the patterns for mortality from other diseases.

"Men generally have a higher mortality at comparable ages, which is considered to be due to a combination of biology and lifestyle. The fact that people with little education or a low income have a higher mortality may largely be due to lifestyle factors including finances -how much one can afford to prioritise one's health. Similarly, we can explain the elevated mortality from COVID-19 for these groups," said Gunnar Andersson.

A number of earlier studies have also shown that single and unmarried people have a higher mortality from various diseases. This is usually to some part explained by selection, meaning that people who have worse health from the beginning are less attractive on the partner market and therefore get married to a lesser degree.
"The explanation is also considered to be in singles having a less protected environment than those who live in a couple relationship. Accordingly, marriage can lead to a healthier life with a lower risk of disease than for the unmarried. This can also explain the elevated risk of dying from COVID-19 for unmarried individuals shown by our study," said Sven Drefahl.

Facts: How the study was done

The study is based on data from the Swedish National Board of Health and Welfare on all registered deaths from COVID-19 in Sweden for adults aged 20 and older, until 7 May 2020. This was combined with register data from Statistics Sweden on city of residence, marital status, country of birth, income, level of education and age. The research is being funded by Forte, the Swedish Research Council for Health, Working Life and Welfare.

Facts: Mortality from COVID-19

Men had more than twice as high a risk of dying from COVID-19 than women.

Unmarried men and women (including those never married, widows/widowers and the divorced) had a 1.5-2 times as high a risk of dying from COVID-19 as those who were married.

Living in the Stockholm area was linked to a 4.5 times as high risk of dying from COVID-19 (for both men and women) compared with the rest of the country.

Those born abroad from low- and middle-income countries in the Middle East and North Africa had twice as high a mortality from COVID-19 for women and 3 times as high for men compared with people born in Sweden.

Those born abroad from low- and middle-income countries outside the Middle East and North Africa had a more than 1.5 times as high mortality from COVID-19.

Men with a compulsory-school and upper-secondary education ran an approximately 25 per-cent higher risk of dying from COVID-19 compared with men with post-upper-secondary education.

Women with a compulsory-school and upper-secondary education ran a 40-50 per-cent higher risk of dying from COVID-19 compared with women with post-upper-secondary education.

FAYETTEVILLE, Ark. -University of Arkansas researchers have established a link between climate patterns in the Amazon and large parts of North and South America using their newly developed tree-ring chronology from the Amazon River basin.

The discovery helps researchers better understand large-scale climate extremes and the impact of the El Niño phenomenon.

Tree growth is a well-established climate proxy. By comparing growth rings in Cedrela odorata trees found in the Rio Paru watershed of the eastern Amazon River with hundreds of similar chronologies in North and South America, scientists have shown an inverse relationship in tree growth, and therefore precipitation patterns, between the areas. Drought in the Amazon is correlated with wetness in the southwestern United States, Mexico and Patagonia, and vice versa.

The process is driven by the El Niño phenomenon, which influences surface-level winds along the equator, researchers said. El Niño is the name given to a large-scale irregularly occurring climate pattern associated with unusually warm water in the Pacific Ocean.

"The new Cedrela chronologies from the Amazon, when compared with the hundreds of tree-ring chronologies in temperate North and South America, document this Pan American resonance of climate and ecosystem extremes in the centuries before widespread deforestation or human-caused climate change," said Dave Stahle, Distinguished Professor of geosciences and first author of a study documenting the findings in the journal Environmental Research Letters.

The connection was not documented until researchers at the University of Arkansas Tree Ring Laboratory, along with colleagues from Brazil and Argentina, developed rainfall reconstructions from growth rings in Cedrela trees. Most rainfall records in the Amazon only date back about 70 years, but Cedrelas live for 200 to 300 years, providing valuable rainfall proxies that pre-date human-influenced climate change. Their work in the Amazon is documented in a short video, and also on a dedicated web site.

In the past 40 years, drought and flood extremes have increased in the Amazon basin, the researchers noted, raising the question of whether human-induced climate change and deforestation are affecting Amazon climate. While that remains an open question, the longer Cedrela-based precipitation record indicates that periods of rainfall extremes occurred in the past and the current extremes might be partly due to natural climate rhythms.

The study will help researchers better understand an area of unequaled biodiversity. The Amazon is home to an estimated 16,000 species of trees and one-tenth of all known species found on the planet, Stahle noted. "The long climate history written in the growth rings of old Cedrela trees in Amazonia will surely be important to the sustainability of the biome."

Meltwater lakes that form at glacier margins cause ice to recede much further and faster compared to glaciers that terminate on land, according to a new study. But the effects of these glacial lakes are not represented in current ice loss models, warn the study authors.

Therefore, estimates of recession rates and ice mass loss from lake-terminating glaciers in the coming decades are likely to be under-estimated.

Many mountain glaciers now terminate in such lakes, formed as meltwater becomes trapped behind ridges of glacier debris. They are known as proglacial lakes. Climate change has increased glacier melt worldwide and this in turn has led to a dramatic increase in the size and number of proglacial lakes. But the effects of proglacial lakes on the rates of deglaciation and on glacier behaviour have previously been poorly understood.

Now, an international team of researchers, led by the University of Leeds, has quantified for the first time the influence of proglacial lakes on mountain glaciers using computer simulations. They found that the presence of a proglacial lake causes a glacier to recede more than four times further and accelerate ice flow by up to eight times when compared to the same glacier terminating on land under the same climate.

The findings, published today in the journal Geophysical Research Letters, show that a land-terminating glacier took 1000 years to succumb to the same amount of recession as a lake-terminating glacier experienced in 100 years.

Study lead author Dr Jenna Sutherland undertook this research while a PhD candidate in the School of Geography at Leeds. She said: "An ice cube in a bowl of water is going to melt much more quickly than an ice cube sitting on a table, and the effect proglacial lakes have on glacier ice is roughly the same.

"The simulations show that the influence of a proglacial lake on a glacier predominantly takes place over decades to centuries rather than over millennia, meaning the glacier recedes much faster than it ever could from climatic changes alone."

Study co-author Dr Jonathan Carrivick, a senior lecturer in geomorphology at Leeds, said: "Our findings suggest that simulations of past, contemporary or future glaciers ignore the effects of ice-contact lakes and will likely mis-represent the timing and rate of recession, especially the changes to the timing and rate that will occur once a proglacial lake forms.

"This effects need to be included in all future models and simulations if we are to have an accurate global picture of glacial ice loss."

The team used the BISICLES ice-flow model, to analyse the effects of a proglacial on the Pukaki Glacier, New Zealand, during recession from the end of the last ice age.

Study co-author James Shulmeister from the University of Canterbury, New Zealand said: "While this study focussed on New Zealand, proglacial lakes are prevalent during glacial retreat worldwide and this paper should therefore be of global interest and importance."

In addition, he noted: "This study is also critical because the timing of ice retreat is often used to determine the synchrony or lack thereof of in climate events globally. Major inferences have been made about the roles of phenomena like oceanic circulation in affecting the global climate system from glacial retreat timings. If the timings are wrong, the relationship between these processes may need to be re-examined."