Culture

(BOSTON) ¬-- Human cells typically transcribe half of their roughly 20,000 genes into RNA molecules at any given time. Just like with proteins, the function of those RNA species not only relies on their abundance but also their precise localization within the 3D space of each cell. Many RNA molecules convey gene information from the cell's nucleus to the protein-synthesizing machinery distributed throughout the cytoplasm (messenger RNAs or mRNAs), others are components of that machinery itself, while still different ones regulate genes and their expression, or have functions that remain to be discovered. Importantly, many diseases including cancer and neurological diseases have signatures that appear as changes in the abundance and distribution of RNAs.

To enable the analysis of a cells' complete collection of RNAs known as their transcriptome in their 3D space (spatial transcriptomics), Wyss Institute synthetic biologists led by Core Faculty member George Church, Ph.D. in 2014 reported FISSEQ, an impactful spatial sequencing technology that is able to simultaneously read the sequences of thousands of those RNAs and visualize their three-dimensional coordinates. However, FISSEQ's powerful ability to sequence this large number of RNA targets on-location comes at a price: its detection efficiency and sensitivity for many of them is relatively low, especially when their expression is low to start with or dialed down in disease.

Now, Church's team has developed a new RNA detection method named BOLORAMIS (short for "Barcoded Oligonucleotides Ligated On RNA Amplified for Multiplexed and parallel In Situ analyses") that overcomes this problem. BOLORAMIS designs and uses a new type of DNA probe that directly binds its RNA target and allows the straight-forward synthesis of a barcoded DNA amplicon, which can be visualized by fluorescent in situ hybridization (FISH) or sequenced in situ. BOLORAMIS enables the analysis of different classes of RNAs with higher specificity and sensitivity than FISSEQ and other methods, works in the context of cells and tissues, and can be highly multiplexed. The study is published in Nucleic Acids Research.

"With BOLORAMIS we have solved some of the challenges that technologies in the spatial transcriptomics field are facing. It gives us a significant advantage for understanding the behavior of molecular networks in normal and pathological processes, and for investigating new drug targets, and developing clinical diagnostics in the native context of tissues that we now can capitalize on," said Church, who is the lead of the Wyss Institute's Synthetic Biology platform, and Professor of Genetics at Harvard Medical School (HMS) and of Health Sciences and Technology at Harvard and MIT.

"The strength of BOLORAMIS lies in the fact that its optimized probes have a very short footprint on RNAs, and that it does away with the need to first generate a DNA replica of RNA molecules in a 'reverse transcriptase' step, which can produce unspecific results and is expensive," said co-first author Songlei Liu, a graduate student working on Church's team.

In FISSEQ, all RNAs are first fixed in place, and then the entire RNA sequence is copied into its complementary DNA sequence (reverse transcription), which is then circularized and amplified into larger balls of DNA. Those can be sequenced and visualized under a specialized fluorescence microscope. "In BOLORAMIS, by bypassing this reverse transcription step, and directly amplifying the RNA signal, we reduce non-specific and false fluorescent signals," said Liu.

BOLORAMIS probes bind like a padlock tightly and with high specificity to a small sequence of only 25 nucleotides in an RNA molecule and thus have a much smaller footprint than other targeted spatial transcriptomics methods, which enhances resolution. In addition, the probes contain barcode sequences that assign a unique molecular zip code to each RNA target species. Upon hybridization of the barcoded padlock probes to RNA, they are circularized and amplified into a tiny amplicon at the target RNA's location, without the need for a reverse transcription step. The amplicon then can be sequenced in situ, or localized with high sensitivity using a second type of probe, known as fluorescent In Situ Hybridization (FISH) probe, which recognizes the multiple barcodes contained in a single amplicon.

The team first explored BOLORAMIS's quantitative capabilities in human induced pluripotent stem cells (iPSCs) by quantifying the levels of 77 mRNAs encoding a range of transcription factors and those of 77 non-coding RNAs with other functions in gene regulation. While BOLORAMIS consistently demonstrated high and localized expression of RNAs that correlate with "stemness" in the cells, it revealed low expression of RNAs that promote differentiation. In a cancer cell line, BOLORAMIS was able to quantitatively trace the location and movements of a non-coding RNA known as MALAT1 that shuttles between two different subcellular locations, the nucleus and cytoplasm. In addition, the researchers demonstrated that BOLORAMIS can trace a common RNA with high sensitivity in cells located in a much more complex tissue environment of cultured human brain organoids.

"It was of critical importance to us to be able to use BOLORAMIS for the multiplexed analysis of many RNAs, which we hoped the new probe design would allow," said co-first author Sukanya Punthambaker, Ph.D., a Postdoctoral Fellow on Church's team. Indeed, a software suite developed by co-author Andrew Pawlowski predicts ideal probes for any gene sequence that then can be synthesized as comprehensive libraries for specific purposes. The team has made this tool available on the GitHub server. "We used a co-culture system of neuronal cells and brain microglia which are known to interact in many normal and disease processes, and targeted 96 different messenger RNAs simultaneously," said Punthambaker. "This allowed us to uncover the spatial relationships between specific cells and RNAs."

"In future research, BOLORAMIS's high functionality in complex human tissues and human-specific organoids may well give us an edge in deciphering RNA signatures related to neurological disorders," added Senior Staff Scientist Jenny Tam, Ph.D., who co-authored the study and integrates some of Church's research activities at the Wyss Institute.

"Assessing the precise locations and levels of RNA molecules within whole cells with the greater efficiency and accuracy that the BOLORAMIS method provides should significantly advance our ability to understand how cell and tissue organization impact normal physiology as well as complex disease states, and hence facilitate development of new therapeutics and diagnostics for innumerable applications," said Wyss Founding Director Donald Ingber, M.D., Ph.D., who is also the Judah Folkman Professor of Vascular Biology at HMS and Boston Children's Hospital, and Professor of Bioengineering at the Harvard John A. Paulson School of Engineering and Applied Sciences.

DALLAS - March 17, 2021 - UT Southwestern researchers have identified the structure of a key member of a family of proteins called nicotinic acetylcholine receptors in three different shapes. The work, published online today in Cell, could eventually lead to new pharmaceutical treatments for a large range of diseases or infections including schizophrenia, lung cancer, and even COVID-19.

Nicotinic acetylcholine receptors are members of a broader super-family of proteins called Cys-loop receptors that function as ion channels on cell surfaces and are found in the membranes of many cell types. When the right molecule settles on these receptors, it opens the gated channels, letting ions flood from the outside to the inside of cells to trigger other cellular processes. Nicotinic acetylcholine receptors respond to acetylcholine, a molecule that nerve cells use to communicate with each other. However, they also respond to other molecules found outside the body, such as nicotine, the essential nutrient choline, and a toxin found on the skin of poison dart frogs called epibatidine.

These receptors, which have been identified in nerve, lung, and immune cells, are connected to conditions such as mental illness, neurodegenerative diseases, lung cancers, and even the destructive immune reactions characteristic of COVID-19 and other infections.

Researchers had previously identified the structures of some members of the Cys-loop super-family, a significant step toward creating drugs that fit onto these ion channels to block or enhance their function. However, say study leaders Colleen M. Noviello, Ph.D., Senior Research Scientist at UTSW, and Ryan E. Hibbs, Ph.D., Associate Professor of Neuroscience and Biophysics at UTSW, the shape, or conformation, of these channels isn't fixed. Cys-loop receptors cycle through three major states during their gating cycle that correspond to when they're closed and waiting to respond to a ligand, or activating molecule (resting state); when they've responded to the ligand and opened for ion flow (open state); or when they are still holding the ligand but have closed again (desensitized state).

After striking out for years to characterize the structure of a key nicotinic acetylcholine receptor called a7, Noviello and Hibbs got a major boost in 2016 after UTSW purchased equipment for cryogenic electron microscopy, or cryo-EM. This technology allows scientists to take photos of biologic molecules at atomic level resolution. When the researchers and their colleagues added to a7 a chaperone protein - a protein that helps support and protect other proteins - it helped a7 retain its proper shape.

With these new tools, the researchers imaged a7 in its different conformations. Because a7's structure is dynamic, allowing it to shift and wiggle, the researchers added different ligands to stabilize it so the cryo-EM images wouldn't be blurry from motion.

When they analyzed these images, Noviello, Hibbs, and their colleagues found several interesting structural features that helped explain some of a7's unusual properties. For example, a negatively charged amino acid in a7's inner channel seems to draw in positively charged calcium from outside cells, explaining why a7 is so permeable to calcium. Also, a curved structure on a7 seems to function as a latch to open the gated channel.

The team says that these newly identified structures for a7 could eventually be used as a template for pharmaceutical companies to develop new medicines that target this and related nicotinic acetylcholine receptors. They plan to continue studying a7 in various cell types and how it interacts with other molecules and proteins.

"The more we know about this important receptor found on so many diverse cell types, the closer we'll get to understanding how it functions in physiology and disease," says Hibbs, an Effie Marie Cain Scholar in Medical Research and member of the Peter O'Donnell Jr. Brain Institute.

Toronto, ON -A new study published in the journal Substance Use and Misuse has found that adverse childhood experiences, such as physical and sexual abuse and neglect, predict greater performance-enhancing substance use in young adults.

Analyzing a sample of over 14,000 U.S. young adults from the National Longitudinal Study of Adolescent to Adult Health, researchers found that adverse childhood experiences are strongly associated with both legal (e.g., creatine monohydrate) and illegal (e.g., anabolic-androgenic steroids) performance-enhancing substance use. This relationship was especially strong among individuals who experienced sexual abuse during childhood, where the likelihood of using anabolic-androgenic steroids increased nine times among men and six times among women.

"Performance-enhancing substance use is common among young adults, despite many adverse outcomes associated with their use, such as the development of eating disorders, muscle dysmorphia, and substance use disorders. To date, we've known relatively little about what may lead to the use of these substances," says lead author Kyle T. Ganson, PhD, MSW, assistant professor at the University of Toronto's Factor-Inwentash Faculty of Social Work. "While it's been documented that adverse childhood experiences are associated with mental health conditions and other substance use behaviors, this study expands our knowledge by now including performance-enhancing substance use."

Over 25% of both men and women in the study reported physical abuse, while roughly 4% reported sexual abuse in childhood. Over 15% of men reported legal performance-enhancing substance use, while 3% reported anabolic-androgenic steroid use. Among both men and women in the study, experiencing all four of the adverse childhood experiences studied had the strongest effect on use of performance-enhancing substance use.

"Our results continue to confirm that experiencing a greater, cumulative number of adverse childhood experiences is strongly associated with poor outcomes. This was particularly true in our study, as both men and women who reported four adverse childhood experiences were significantly more likely to report performance-enhancing substance use," says Ganson.

Being the first known study to investigate such associations between adverse childhood experiences and performance-enhancing substance use, this article's conclusions add to the growing understanding of risk factors of performance-enhancing substance use, as well as add to the literature on the effects of childhood trauma.

"Experiencing childhood abuse may lead to a desire to develop a large, muscular body to protect against future interpersonal trauma, and young people commonly use performance-enhancing substances to build muscle.," says senior author Jason M. Nagata, MD, MSc, assistant professor at the University of California, San Francisco's Department of Pediatrics. "In addition to other adverse health outcomes, legal performance-enhancing substance use has been linked to anabolic steroid use, which can lead to irritability, aggression, poor mental health, heart disease, and liver damage."

This study provides further insight into the importance of monitoring for potential performance-enhancing substance use among patients with reported adverse childhood experiences, in addition to providing psychoeducation regarding the consequences associated with performance-enhancing substance use.

"Medical and mental health professionals should be aware of the common use of performance-enhancing substances, particularly among boys and men. Screening for performance-enhancing substance use and adverse childhood experiences should be a regular occurrence," says Ganson. "We also need to ensure that current public policy is informed by research to protect the health and well-being of adolescents and young adults from the adverse outcomes associated with adverse childhood experiences and the dangers of performance-enhancing substance use."

(March 17, 2021) -- Eric Shattuck, assistant professor of research in the UTSA Institute for Health Disparities Research (IHDR) at The University of Texas at San Antonio, is studying the phenomenon of social distancing in response to infectious disease and its effects on pathogen transmission and the health of individuals and communities.

Many animals, including humans, exhibit behavioral changes during the early stages of an infection, including reduced social contacts, called sickness behavior. His findings suggest innate social distancing might help prevent the infection from spreading within social groups.

"The similarities between public health directives and what we see operating on a biological level in nature is remarkable, Shattuck said.

"For instance, we've been advised to keep 6 feet apart from others to prevent COVID transmission in case they're asymptomatic carriers of the virus. We know that some ants have a similar strategy, where individual ants increase their physical distance to others after they recognize that there is a possible infection in the colony" Shattuck added. "This shows us that some of the most basic interventions, like social distancing, can be highly effective at preventing outbreaks, whether of COVID-19, flu, or other pathogens."

This research has been at the center of a study titled "Infectious Diseases and Social Distancing in Nature," the manuscript for which has been published in the journal Science. Shattuck collaborated with researchers from universities and research centers across the country and in the United Kingdom.

While the other authors have research interests in vampire bats, rodents, insects and more, Shattuck is the only author who studies humans.

"Because humans are highly social creatures with complex and varied cultures -- and because culture can affect both our biology and the way that we interpret physical and emotional sensations -- I use an anthropological framework that focuses on human biological and cultural variation," Shattuck said about his research on sickness behavior.

He added that this study can start important conversations across scientific fields about integrating these normal biological responses into our thinking about disease transmission and public health. "People should listen to their bodies if they think they might be sick but we also need to work to ensure that rest, recuperation and isolation aren't stigmatized or otherwise prevented. Shattuck said"

In his role with IHDR, Shattuck explores various research projects to further the mission of the Institute: to reduce and eliminate health disparities in South Texas through integration of biomedical and socio-behavioral science approaches.

Another project he's working on investigating the beneficial effects of hospital arts programs on mood, pain and nausea in adult cancer patients. Along with members of the UTSA music faculty, Drs. Tracy Cowden and John Nix, Shattuck is working with a San Antonio non-profit, Hearts Need Art, to collect data.

A groundbreaking new study led by University of Minnesota Twin Cities researchers from both the College of Science and Engineering and the Medical School shows for the first time that lab-created heart valves implanted in young lambs for a year were capable of growth within the recipient. The valves also showed reduced calcification and improved blood flow function compared to animal-derived valves currently used when tested in the same growing lamb model.

If confirmed in humans, these new heart valves could prevent the need for repeated valve replacement surgeries in thousands of children born each year with congenital heart defects. The valves can also be stored for at least six months, which means they could provide surgeons with an "off the shelf" option for treatment.

The study was published today in Science Translational Medicine, an interdisciplinary medical journal by the American Association for the Advancement of Science (AAAS). The valve-making procedure has also been patented and licensed to the University of Minnesota startup company Vascudyne, Inc. (Stillwater, Minn.).

"This is a huge step forward in pediatric heart research," said Robert Tranquillo, the senior researcher on the study and a University of Minnesota professor in the Departments of Biomedical Engineering and the Department of Chemical Engineering and Materials Science. "This is the first demonstration that a valve implanted into a large animal model, in our case a lamb, can grow with the animal into adulthood. We have a way to go yet, but this puts us much farther down the path to future clinical trials in children. We are excited and optimistic about the possibility of this actually becoming a reality in years to come."

Currently, researchers have not been able to develop a heart valve that can grow and maintain function for pediatric patients. The only accepted options for these children with heart defects are valves made from chemically treated animal tissues that often become dysfunctional due to calcification and require replacement because they don't grow with the child. These children will often need to endure up to five (or more) open heart surgeries until a mechanical valve is implanted in adulthood. This requires them to take blood thinners the rest of their lives. 

In this study, Tranquillo and his colleagues used a hybrid of tissue engineering and regenerative medicine to create the growing heart valves. Over an eight-week period, they used a specialized tissue engineering technique they previously developed to generate vessel-like tubes in the lab from a post-natal donor's skin cells. To develop the tubes, researchers combined the donor sheep skin cells in a gelatin-like material, called fibrin, in the form of a tube and then provided nutrients necessary for cell growth using a bioreactor. 

The researchers then used special detergents to wash away all the sheep cells from the tissue-like tubes, leaving behind a cell-free collagenous matrix that does not cause immune reaction when implanted. This means the tubes can be stored and implanted without requiring customized growth using the recipient's cells.

The next step was to precisely sew three of these tubes (about 16 mm in diameter) together into a closed ring. The researchers then trimmed them slightly to create leaflets to replicate a structure similar to a heart valve about 19 mm in diameter.

Video: https://www.youtube.com/watch?v=zpRbFsAVofA

"After these initial steps, it looked like a heart valve, but the question then became if it could work like a heart valve and if it could grow," Tranquillo said. "Our findings confirmed both."

This second generation of tri-tube valves were implanted into the pulmonary artery of three lambs. After 52 weeks, the valve regenerated as its matrix became populated by cells from the recipient lamb, and the diameter increased from 19 mm to a physiologically normal valve about 25 mm. The researchers also saw a 17 to 34 percent increase in the length of the valve leaflets as measured from ultrasound images. In addition, researchers showed that the tri-tube valves worked better than current animal-derived valves with almost none of the calcification or blood clotting that the other valves showed after being implanted in lambs of the same age.

"We knew from previous studies that the engineered tubes have the capacity to regenerate and grow in a growing lamb model, but the biggest challenge was how to maintain leaflet function in a growing valved conduit that goes through 40 million cycles in a year," said Zeeshan Syedain, the lead researcher on the study and a University of Minnesota senior research associate in Tranquillo's lab. "When we saw how well the valves functioned for an entire year from young lamb to adult sheep, it was very exciting."

https://www.youtube.com/watch?v=rme9CZgRgsg

Tranquillo said the next steps are to implant the tri-tube valve directly into the right ventricle of the heart to emulate the most common surgical repair and then start the process of requesting approval from the U.S. Food and Drug Administration (FDA) for human clinical trials over the next few years. 

"If we can get these valves approved someday for children, it would have such a big impact on the children who suffer from heart defects and their families who have to deal with the immense stress of multiple surgeries," Tranquillo said. "We could potentially reduce the number of surgeries these children would have to endure from five to one. That's the dream."

MEMPHIS, Tenn. - Non-Hispanic black patients with Type 1 diabetes and COVID-19 were almost four times as likely to present to the hospital with diabetic ketoacidosis (DKA) compared to non-Hispanic whites, according to an article published in The Journal of Clinical Endocrinology & Metabolism by Le Bonheur Pediatric Endocrinologist Kathryn Sumpter, MD.

The study examined 180 patients with Type 1 diabetes and laboratory-confirmed COVID-19 from 52 clinical sites, including Le Bonheur Children's. The objective of the study was to evaluate instances of DKA, a serious complication of Type 1 diabetes, in patients with Type 1 diabetes and COVID-19 and determine if minorities had increased risk when controlled for sex, age, insurance and last hemoglobin A1c (HbA1c) level.

"We know that Type 2 diabetes is a risk factor for worse COVID-19 outcomes, but less is known about Type 1 diabetes and COVID," said Sumpter. "This study allowed us to examine the intersection of Type 1 diabetes and COVID while also determining the racial inequities in DKA for these patients."

Previous studies have shown that COVID-19 disproportionately affects racial and ethnic minority groups with higher rates of infection and death. The same minority groups with Type 1 diabetes have also been shown to have increased risk of DKA and associated mortality. Because of these existing risk factors, it is critical to understand how COVID-19 and Type 1 diabetes interact and affect outcomes. The results of this study show that non-Hispanic black patients with COVID-19 and Type 1 diabetes have an additional risk of DKA beyond the risk of having diabetes or being of minority status.

The results of the study show that non-Hispanic blacks were more likely to present with DKA and COVID-19 (55%) compared with non-Hispanic whites (13%). Hispanics had almost two times greater odds of presenting with DKA compared to non-Hispanic whites, which researchers found to not be statistically significant.

"A combination of factors lead to higher rates of DKA among minority Type 1 diabetes patients with COVID-19 that relate to social and structural risks," said Sumpter. "Social determinants of health, including income level, education, racial discrimination and inadequate health care access, impact these populations with devastating complications for Type 1 diabetes and COVID-19."

According to the study, intervention in these areas is essential to prevent these poor outcomes that unequally affect minority populations.

The coronavirus' structure is an all-too-familiar image, with its densely packed surface receptors resembling a thorny crown. These spike-like proteins latch onto healthy cells and trigger the invasion of viral RNA. While the virus' geometry and infection strategy is generally understood, little is known about its physical integrity.

A new study by researchers in MIT's Department of Mechanical Engineering suggests that coronaviruses may be vulnerable to ultrasound vibrations, within the frequencies used in medical diagnostic imaging.

Through computer simulations, the team has modeled the virus' mechanical response to vibrations across a range of ultrasound frequencies. They found that vibrations between 25 and 100 megahertz triggered the virus' shell and spikes to collapse and start to rupture within a fraction of a millisecond. This effect was seen in simulations of the virus in air and in water.

The results are preliminary, and based on limited data regarding the virus' physical properties. Nevertheless, the researchers say their findings are a first hint at a possible ultrasound-based treatment for coronaviruses, including the novel SARS-CoV-2 virus. How exactly ultrasound could be administered, and how effective it would be in damaging the virus within the complexity of the human body, are among the major questions scientists will have to tackle going forward.

"We've proven that under ultrasound excitation the coronavirus shell and spikes will vibrate, and the amplitude of that vibration will be very large, producing strains that could break certain parts of the virus, doing visible damage to the outer shell and possibly invisible damage to the RNA inside," says Tomasz Wierzbicki, professor of applied mechanics at MIT. "The hope is that our paper will initiate a discussion across various disciplines."

The team's results appear online in the Journal of the Mechanics and Physics of Solids. Wierzbicki's co-authors are Wei Li, Yuming Liu, and Juner Zhu at MIT.

A spiky shell

As the Covid-19 pandemic took hold around the world, Wierzbicki looked to contribute to the scientific understanding of the virus. His group's focus is in solid and structural mechanics, and the study of how materials fracture under various stresses and strains. With this perspective, he wondered what could be learned about the virus' fracture potential.

Wierzbicki's team set out to simulate the novel coronavirus and its mechanical response to vibrations. They used simple concepts of the mechanics and physics of solids to construct a geometrical and computational model of the virus' structure, which they based on limited information in the scientific literature, such as microscopic images of the virus' shell and spikes.

From previous studies, scientists have mapped out the general structure of the coronavirus -- a family of viruses that s HIV, influenza, and the novel SARS-CoV-2 strain. This structure consists of a smooth shell of lipid proteins, and densely packed, spike-like receptors protruding from the shell.

With this geometry in mind, the team modeled the virus as a thin elastic shell covered in about 100 elastic spikes. As the virus' exact physical properties are uncertain, the researchers simulated the behavior of this simple structure across a range of elasticities for both the shell and the spikes.

"We don't know the material properties of the spikes because they are so tiny -- about 10 nanometers high," Wierzbicki says. "Even more unknown is what's inside the virus, which is not empty but filled with RNA, which itself is surrounded by a protein capsid shell. So this modeling requires a lot of assumptions."

"We feel confident that this elastic model is a good starting point," Wierzbicki says. "The question is, what are the stresses and strains that will cause the virus to rupture?"

A corona's collapse

To answer that question, the researchers introduced acoustic vibrations into the simulations and observed how the vibrations rippled through the virus' structure across a range of ultrasound frequencies.

The team started with vibrations of 100 megahertz, or 100 million cycles per second, which they estimated would be the shell's natural vibrating frequency, based on what's known of the virus' physical properties.

When they exposed the virus to 100 MHz ultrasound excitations, the virus' natural vibrations were initially undetectable. But within a fraction of a millisecond the external vibrations, resonating with the frequency of the virus' natural oscillations, caused the shell and spikes to buckle inward, similar to a ball that dimples as it bounces off the ground.

As the researchers increased the amplitude, or intensity, of the vibrations, the shell could fracture -- an acoustic phenomenon known as resonance that also explains how opera singers can crack a wineglass if they sing at just the right pitch and volume. At lower frequencies of 25 MHz and 50 MHz, the virus buckled and fractured even faster, both in simulated environments of air, and of water that is similar in density to fluids in the body.

"These frequencies and intensities are within the range that is safely used for medical imaging," says Wierzbicki.

To refine and validate their simulations, the team is working with microbiologists in Spain, who are using atomic force microscopy to observe the effects of ultrasound vibrations on a type of coronavirus found exclusively in pigs. If ultrasound can be experimentally proven to damage coronaviruses, including SARS-CoV-2, and if this damage can be shown to have a therapeutic effect, the team envisions that ultrasound, which is already used to break up kidney stones and to release drugs via liposomes, might be harnessed to treat and possibly prevent coronavirus infection. The researchers also envision that miniature ultrasound transducers, fitted into phones and other portable devices, might be capable of shielding people from the virus.

Wierzbicki stresses that there is much more research to be done to confirm whether ultrasound can be an effective treatment and prevention strategy against coronaviruses. As his team works to improve the existing simulations with new experimental data, he plans to zero in on the specific mechanics of the novel, rapidly mutating SARS-CoV-2 virus.

"We looked at the general coronavirus family, and now are looking specifically at the morphology and geometry of Covid-19," Wierzbicki says. "The potential is something that could be great in the current critical situation."

A new study has found that about 35% of Americans with a cancer history had an elevated risk of cardiovascular disease in the next decade, compared with about 23% of those who didn't have cancer.

Based on a risk calculator that estimates a person's 10-year chances of developing heart disease or stroke, researchers from The Ohio State University found that the average estimated 10-year risk for a cancer survivor was about 8%, compared to 5% for those who didn't have a history of cancer.

The new study appears in the journal PLOS ONE.

"We know that obesity, cancer and cardiovascular disease share some common risk factors, and in addition to those shared risk factors, cancer patients also receive treatments including radiation and chemotherapy that can affect their cardiovascular health - we call that cardiotoxicity," said lead researcher Xiaochen Zhang, a PhD candidate in Ohio State's College of Public Health.

But those risks may be underestimated or poorly understood, leading Zhang and fellow researchers to urge steps to boost recognition among health care providers and their patients.

"The good news is that we're getting really good at treating cancer and we have more survivors, but we need to start thinking more carefully about the non-cancer risks following a diagnosis, one of which is cardiovascular disease," said study senior author Ashley Felix, an associate professor of epidemiology at Ohio State.

"We don't want people to survive cancer only to die prematurely of heart disease or stroke, so we need to make sure that cancer patients, and their health care team, are aware of this increased risk."

The data used in the study comes from the National Health and Nutrition Examination Survey conducted by the Centers for Disease Control and Prevention. The nationally representative sample of people surveyed from 2007 to 2016 should provide a good picture of the elevated risk for cancer survivors in the U.S., the researchers said.

For this analysis, they examined data provided by 15,095 adults aged 40 to 79 years with no history of cardiovascular disease. Almost 13% reported a history of cancer.

One of the strengths of this research is the large study size, which allowed for analysis based on type of cancer and by age group. Survivors of testicular, prostate, bladder and kidney cancers had particularly high 10-year cardiovascular disease risk, as did those in their 60s.

When the researchers compared individual cardiovascular disease risk factors by cancer status, they found that older age, higher systolic blood pressure and a personal history of diabetes were more common in the cancer survivors.

Looking forward, it's important that researchers and health care providers keep their eyes on the growing number of cancer survivors, including younger adults, Felix said. Almost 17 million Americans live with a cancer diagnosis, a number that is expected to grow to 26 million by 2040.

"If we continue to see the increasing incidence of cancer among younger adults, we can expect to see a larger burden of cardiovascular disease among those individuals - our future studies need to go in that direction," she said.

Added Zhang, "The good news is that those younger individuals have a lot of time to make lifestyle changes that could move their cardiovascular risk in a positive direction.

"In addition to monitoring cancer survivors carefully for cardiovascular disease - and making them aware of the elevated risk - health care providers have the opportunity to guide patients toward interventions that can lower their risk," she said.

There's also potential for developing a risk-assessment tool that specifically takes cancer survivorship into account - which would allow for more precise assessments for that population, the researchers said.

BOSTON - March 16, 2021 - The fast-spreading UK, South Africa, and Brazil coronavirus variants are raising both concerns and questions about whether COVID-19 vaccines will protect against them. New work led by Bing Chen, PhD, at Boston Children's Hospital analyzed how the structure of the coronavirus spike proteins changes with the D614G mutation -- carried by all three variants -- and showed why these variants are able to spread more quickly. The team reports its findings in Science (March 16, 2020).

Chen's team imaged the spikes with cryo-electron microscopy (cryo-EM), which has resolution down to the atomic level. They found that the D614G mutation (substitution of in a single amino acid "letter" in the genetic code for the spike protein) makes the spike more stable as compared with the original SARS-CoV-2 virus. As a result, more functional spikes are available to bind to our cells' ACE2 receptors, making the virus more infectious.

Preventing spikes' shape change

In the original coronavirus, the spike proteins would bind to the ACE2 receptor and then dramatically change shape, folding in on themselves. This enabled the virus to fuse its membrane with our own cells' membranes and get inside. However, as Chen and colleagues reported in July 2020, the spikes would sometimes prematurely change shape and fall apart before the virus could bind to cells. While this slowed the virus down, the shape change also made it harder for our immune system to contain the virus.

"Because the original spike protein would dissociate, it was not good enough to induce a strong neutralizing antibody response," says Chen.

When Chen and colleagues imaged the mutant spike protein, they found that the D614G mutation stabilizes the spike by blocking the premature shape change. Interestingly, the mutation also makes the spikes bind more weakly to the ACE receptor, but the fact that the spikes are less apt to fall apart prematurely renders the virus overall more infectious.

"Say the original virus has 100 spikes," Chen explains. "Because of the shape instability, you may have just 50 percent of them functional. In the G614 variants, you may have 90 percent that are functional, so even though they don't bind as well, the chances are greater that you will have infection."

Chen proposes that redesigned vaccines incorporate the code for this mutant spike protein. The more stable spike shape should make any vaccine based on the spike (as are the Moderna, Pfizer, and Johnson & Johnson vaccine) more likely to elicit protective neutralizing antibodies, he says.

Future direction: A drug to block coronavirus entry

Chen and his colleagues are further applying structural biology to better understand how SARS-CoV-2 binds to the ACE2 receptor, with an eye toward therapeutics to block the virus from gaining entry to our cells.

In January, the team showed in Nature Structural & Molecular Biology that a structurally-engineered "decoy" ACE2 protein binds the virus 200 times more strongly than the body's own ACE2. The decoy potently inhibited the virus in cell culture, suggesting it could be an anti-COVID-19 treatment. Chen is now planning to advance this research into animal models.

A new study comparing decades of environmental monitoring records has confirmed that Canada's caribou are not faring as well as other animals like moose and wolves in the same areas--and also teased out why.

The study used 16 years of data to examine changes in vegetation, moose, wolves and caribou.
"Caribou are declining across Canada and have been recently lost in the Lower 48 States," says Melanie Dickie, a doctoral student with UBC Okanagan's Irving K. Barber Faculty of Science.

"Understanding why caribou are declining is the first step to effectively managing the species--it tells us which parts of the issue we can target with management actions and how that might help caribou."

Dickie, along with fellow UBCO researchers Dr. Clayton Lamb and Dr. Adam Ford, describe the decline in caribou populations as an ecological puzzle. Typically, there are multiple factors, all changing at once, making it hard to identify how the pieces fit together. Factors such as predation from wolves and other large carnivores, increasing moose and deer populations, and habitat alteration through resource extraction and wildfires all play a part. The study aimed to sort out the roles each of these play in caribou population declines.

Once land is cleared by either wildfire or harvesting, the mature forest transforms into more productive early seral forage. With the tree canopy removed, there is a significant increase in sunlight, allowing understory plants to thrive. These plants provide food that benefits moose, deer and their predators. These predators then have a spillover effect on the rarer caribou, creating apparent competition between moose and caribou.

"Changes in primary productivity have the potential to substantially alter food webs, with positive outcomes for some species and negative outcomes for others," Dickie explains. "Understanding the environmental context and species interactions that give rise to these different outcomes is a major challenge to both theoretical and applied ecology."

To establish the link between habitat alteration and primary productivity, the researchers first examined satellite imagery to show a link between logging and new vegetation growth. They then used data on moose, caribou and wolf numbers to compare the leading hypotheses on how changes in vegetation influence these populations. The analysis was conducted across a 598,000-square kilometre area located in the boreal shield and boreal plains of western Canada.

Ultimately, the researchers determined that lower caribou populations were a victim of an ecological chain reaction. Caribou have a lower population growth rate relative to moose, making them more susceptible to landscape changes.

"We found that increased deciduous vegetation on the landscape, which moose like to eat, increased moose populations, which increased wolves, and in turn, means declining caribou," Dickie says. "We also found that human land use, like forestry, significantly increased vegetation productivity, suggesting that these kinds of land uses are leading to caribou declines via changes to predators and prey."

Caribou conservation will be a defining point for Canada in the 21st century, adds Dr. Lamb, a Liber Ero Fellow at UBCO. Caribou highlight an unresolved tension between land stewardship, wildlife conservation and resource extraction. Further, as caribou populations continue to decline, Indigenous Peoples are forced to grapple with mounting threats to food security, cultural traditions, and infringed treaty rights.

"We can't attribute caribou declines to just one factor or another," he says. "But understanding the relative importance of these factors, and how they interact, can help us understand how we can manage caribou populations in the face of continued climate change and land use."

Native reptile populations on Christmas Island have been in severe decline with two species, Lister's gecko and the blue-tailed skink, entirely disappearing from the wild. While previously the main driver for this decline is likely predation by invasive species and habitat destruction, a silent killer is now threatening to wipe the species out entirely.

Those bred in captivity on the Australian Territory in the Indian Ocean have also been mysteriously dying, leaving the two species - which number only around 1000 each - in danger of extinction. Veterinary scientists from the University of Sydney, the Australian Registry of Wildlife Health and the Taronga Conservation Society Australia have now discovered the cause of these deaths: a bacterium, Enterococcus lacertideformus (E. lacertideformus).

The bacterium was discovered in 2014 after captive reptiles presented with facial deformities and lethargy, and some even died. Samples were collected and analysed using microscopy and genetic testing.

The researchers' findings, published in Frontiers in Microbiology, will inform antibiotic trials on the reptiles to see if the infection can be treated.

The bacterium grows in the animal's head, then in its internal organs, before eventually causing death. It can be spread by direct contact - including through reptiles' mouths, or via reptiles biting one another - often during breeding season fights.

"This means that healthy captive animals need to be kept apart from infected ones and should also be kept away from areas where infected animals have been," said Jessica Agius, co-lead researcher and PhD candidate in the Sydney School of Veterinary Science.

Ms Agius and the research team not only identified the bacterium, they decoded its genetic structure using whole genome sequencing.

Specific genes were identified that are likely to be associated with the bacterium's ability to infect its host, invade its tissues and avoid the immune system.

"We also found that the bacterium can surround itself with a biofilm - a 'community of bacteria' that can help it survive," Ms Agius said.

"Understanding how E. lacertideformus produces and maintains the biofilm may provide insights on how to treat other species of biofilm-forming bacteria."

The search of the genetic code suggested that the killer bacterium was susceptible to most antibiotics.

Professor David Phalen, research co-lead and Ms Agius' PhD supervisor, said: "This suggests that infected animals might be successfully treated. That's what we need to determine now."

In another effort to protect the endangered reptiles on Christmas Island, a population of blue-tailed skinks has been established on the Cocos Islands. Ms Agius played a critical role in the translocation, testing reptiles on the Cocos Islands to make sure that they were free of E. lacertideformus.

"It's critical we act now to ensure these native reptiles survive," Ms Agius said.

The research team led by Prof. YANG Lihua from Hefei National Laboratory for Physical Sciences at the Microscale, School of Chemistry and Materials Science of the University of Science and Technology of China (USTC) of the Chinese Academy of Sciences proposed nanomicelles composed solely of macromolecules as a new approach for treating pancreatic tumor. The study was published in ACS Applied Materials & Interfaces.

Host dense peptides (HDP) is a part of the innate immunity of eukaryotic organism. It helps the host fence back attack by microbes through disrupting cellular membrane integrity. Inspired by HDP, membrane-disruptive macromolecules are designed with two most HDP's common structural characteristics (cationic and amphipathic) to realize similar membrane-disrupting function so that drug-resistant cancer cells can be efficiently eliminate. The onset of drug resistance is delayed after repeat treatment, suggesting the potential for addressing the cancer resistance issue.

Despite these advantages, membrane-disruptive macromolecules normally cannot distinguish cancerous from normal cells. How to make membrane-disruptive macromolecules preferentially active to cancerous cells over normal cells is a significant challenge.

In this study, the researchers used an acid-sensitive, membrane-disruptive micelle (M-14K) as the model for such nanoparticles.

This long-circulating nanoparticle showed acid-activated cytotoxicity indiscriminately to both cancerous and fibroblast cells, which is realized by acid-activatable disruption of cellular membrane integrity. The ability of such nanoparticles to penetrate the stromal barrier and eliminate the sheltered cancer cells was verified both in vitro using three-dimensional (3D) cell spheroids and in vivo using mouse models bearing BxPC-3 tumors.

Notably, through animal experiments, the researchers found that the expression of extracellular matrix components was significantly suppressed, the tumor tissue was transformed into a less dense structure, and stroma was remodeled, without promoting tumor metastasis.

Using acid-responsive nanoparticles composed solely of membrane-disruptive macromolecules, stroma remodeling and cancerous cells elimination can be realized simultaneously. This approach may open a new avenue for the development of efficacious drugs inhibiting pancreatic tumor growth and metastasis.

What makes pancreatic tumor hard to cure is the dense stromal barriers sheltering cancerous cells. The penetration of drugs is hindered. To promote the infiltration of therapeutics, an adjuvant is used prior to gemcitabine to remodel the stroma. Nevertheless, this widely studied strategy may raise the risk of tumor metastasis and tumor cells' resistance to drugs.

TORONTO, ON - American adults 65 years old and older have better vision than that age group did nearly a decade ago, according to a recent study published in the journal Ophthalmic Epidemiology.

In 2008, 8.3% of those aged 65 and older in the US reported serious vision impairment. In 2017 that number decreased to 6.6% for the 65-plus cohort. Put another way: if vision impairment rates had remained at 2008 levels, an additional 848,000 older Americans would have suffered serious vision impairment in 2017.

"The implications of a reduction in vision impairment are significant," says the study's first author, University of Toronto pharmacy student, ZhiDi (Judy) Deng.

"Vision problems are a major cause of age-related disability, and serious vision impairment can increase the risk of falls and fractures and undermine quality of life. Moreover, the cost of vision impairment to the US economy is in the tens of billions of dollars. We need to determine how to maintain this positive trajectory into the next decade and beyond."

Racial/Ethnic disparities in vision health decreased

For every year between 2008 and 2017, serious vision impairment was more prevalent among Black and Hispanic respondents aged 65 and older than among non-Hispanic White respondents; however, these racial/ethnic health disparities appear to be narrowing.

Black and Hispanic Americans over 65 showed greater reductions in vision impairment across the decade compared to Non-Hispanic White Americans, with a 27% decline in serious vision impairment among Black respondents and a 24% decline among Hispanic Americans. Non-Hispanic White Americans showed the smallest decline in serious vision impairment at 13%.

"The narrowing of racial/ethnic disparities in vision related problems during this period may be attributable, in part, to the implementation of the Affordable Care Act which led to a large increase in the percentage of insured Hispanics and Black Americans," says Deng.

"While it is heartening to see the racial disparities improving over the decade, targeted outreach and improved access to affordable vision care for racialized groups is still urgently needed to effectively eliminate the gap."

The greatest improvement in vision occurred in those aged 85 and older

The observed decade decline in vision problems was propelled by a 26% decrease in the odds of vision impairment among those aged 85 and older, and a 16% decline among those aged 75-84 when adjustments were made for age, sex, and race/ethnicity. In contrast, the 65 to 74-year-old cohort had a much more modest improvement compared to their 2008 counterparts, experiencing only a 2.6% decline over the decade.

"Although a 21% decline in the odds of vision impairment over a 10-year period is truly phenomenal, we cannot assume this trend will continue at the same pace," says senior author, Esme Fuller Thomson, director of University of Toronto's Institute of Life Course and Aging and professor at the Factor-Inwentash Faculty of Social Work, the Department of Family & Community Medicine and the Bloomberg Faculty of Nursing.

"The very small gains made by those currently aged 65 to 74 over the past decade suggest that as the Baby Boom cohort ages into their late 70s and 80s, the downward trend in the future may be much less steep than that seen from 2008 to 2017."

Vision improvements among women drives change

Women account for nearly two-thirds of global blindness. In this study, women had a higher prevalence of vision impairment compared to men, but this gap narrowed over the decade. The rate of decline in the odds of impairment over the decade was consistently greater for women (21%) than for men (9%). It is unclear why the rate of improvement differs by gender, but previous research suggest women are more likely than men to visit eye care professionals, which may contribute to these findings.

Causes remain a medical mystery

The observed downward trajectory in vision problems among older adults is in keeping with previous studies using smaller samples in the United States and Europe, but the reason for such a dramatic decrease remains a medical mystery.

The study's authors hypothesize several potential causes for the observed improvements, including advances in medical interventions for vision problems, better management of comorbid health conditions such as diabetes, cohort differences in lifelong access to vaccinations and antibiotics, universal folic acid supplementation, decreases in periodontitis, and improvements in air pollution, including lower life-time exposure to lead due to the phase-out of leaded gasoline. However, the design of this study and earlier research do not provide definitive insight into the causes of the observed positive trend in the prevalence of serious vision problems.

The study was based on 10 consecutive waves of the American Community Survey (2008-2017) which engaged a nationally representative sample of approximately half a million American respondents aged 65 and older annually, including those who lived in institutions such as long-term care homes, and those who were living in the community. The question on vision impairment was "Is this person blind or does he/she have serious difficulty seeing even when wearing glasses?"

"It is truly remarkable that there would have been an additional 848,000 older Americans with serious vision impairment in 2017 if the rates had remained at 2008 levels," says Fuller-Thomson. "We need more research to understand why these trends are occurring."

NEW YORK (March 17, 2021) -- High speed air dryers not only leave more contamination on poorly washed hands compared to paper towels, but during hand drying, they can also spread germs onto clothing, ultimately transferring more bacteria to other surfaces, according to a study published today in Infection Control & Hospital Epidemiology, the journal of the Society for Healthcare Epidemiology of America.

Past research has shown recommended handwashing practices for healthcare workers are often not followed with average adherence of 40%. To better understand the impact of hand drying in hand hygiene, researchers conducted an experiment to learn the role of different hand drying methods in spreading germs from poorly washed hands beyond the restroom.

For the study, volunteers sanitized their hands with 70% alcohol disinfectant, dipped them in a nonharmful viral solution, shook them off, and then dried them either using an air dryer or paper towels. During experiment, volunteers wore an apron to test contamination of clothing. Volunteers then took a predetermined path through the hospital touching commonly used surfaces, such as elevator buttons, along the way. Samples were collected from surfaces that volunteers touched and also from the aprons.

"Based on the user and surface contamination observed following hand drying using high speed air dryers, we question the choice of air dryers in healthcare settings," said Ines Moura, PhD, research fellow, University of Leeds and an author on the study. "Microbes remaining after hand drying can transfer to surfaces via contaminated hands and clothing."

On average, the levels of contamination to surfaces volunteers touched with their hands were 10 times higher after hands were dried with an air dryer than with paper towels. Researchers also saw greater microbial transfer to the apron when volunteers used the air dryer. The transfer of microbes to volunteers' clothing after using the air dryer also contributed to the spread of germs.

"The study was performed in a healthcare setting and has important lessons for health institutions that still have high speed air dryers in restrooms, but the results are also relevant for public restrooms with high foot traffic," Moura said.

- The increasing complexity of treatments for lung cancer and language differences can make it difficult for patients to communicate with their medical teams

- Risks of jeopardising the treatment and care journey as well as recent progress in patient empowerment.

Lugano, Switzerland; Denver, CO, USA, 17 March 2021 - More than one in 10 patients with lung cancer do not know what type of tumour they have, according to data from a 17-country study carried out by the Global Lung Cancer Coalition (GLCC) to be presented at the European Lung Cancer Conference (ELCC) (1). Nearly one in five patients surveyed did not feel involved in decisions about their treatment and care, and a similar proportion felt that they had never or only sometimes been treated with dignity and respect by those treating them.

"I was shocked that some people didn't know what type of lung cancer they had because, if they didn't have that information, how could they understand their treatment options for making decisions about their care?" said Vanessa Beattie from the GLCC. "Receiving a diagnosis of lung cancer is devastating and it's crucial that patients receive good quality information from the start so they are empowered to make informed decisions about their treatment. At diagnosis, they should be offered information - written or in another form - about their type and stage of cancer and a potential treatment plan which they can discuss with their cancer team and their family."

Of 907 patients with lung cancer who responded to the survey carried out in January 2020, 574 (63%) were from Europe. Of European respondents, 11% did not know what type of lung cancer they had (13% globally), 19% did not feel involved in decisions about their treatment and care (18% globally), and 11% felt they had 'never' or only 'sometimes' been treated with dignity and respect by their treatment team (9% globally).

Beattie suggested that, while cancers services may vary across Europe and globally, clinicians need to keep challenging themselves to drive improvements in lung cancer care and engage with patients to address their individual needs.

"There is still a stigma attached to lung cancer because of its links with smoking, but every patient should be treated with dignity and respect at all times and have a positive experience of care wherever they are treated, including opportunities to talk about their concerns," said Beattie.

Language differences and the increasing complexity of treatments for lung cancer can make it difficult for patients to communicate with their medical team and this may jeopardise not only their care but also recent progress in patient empowerment.

A second study to be presented at ELCC highlights the significant need for interpreters at cancer clinics. Between November 2017 and December 2020, 242 referrals for interpreters speaking a total of 24 languages were arranged at a major hospital in Ireland (2). The majority were for patients from Central and Eastern Europe and the number of interpreter requests ranged from 0-18 per patient. The significant number of referrals reflect the fact that one in six people resident in Ireland were born abroad, and three quarters of these speak their primary language at home, with 20% of those aged 65 and over having little or no English (3).

"A lack of patient understanding of their disease is a major issue especially for those with lung cancer as there have been a lot of recent advances in targeted therapies which patients take at home rather than in hospital. If there is a language barrier, patients may miss appointments or take their medicines incorrectly which can affect their prognosis and quality of life," said lead investigator, Dr Tianna Martin, from Beaumont Hospital, Dublin, Ireland.

She pointed out how easily misunderstandings can occur and stressed the importance of asking patients their preferred language especially when they come from countries where multiple languages are spoken.

"It's really heart-breaking to see a patient who appeared to understand their diagnosis and treatment become deeply distressed weeks or months later when they finally realise they have cancer," she said.

Martin suggested that records of patients with language needs should be flagged 'at risk' so that clinicians check carefully to ensure that appropriate translation services are in place. She also proposed that, given the growing complexity of lung cancer treatments, specialised training should be given to interpreters at cancer clinics.

"It is important that interpreters can accurately explain the diagnosis and treatment options at all stages of the disease so that patients can make really informed decisions and, with the rise in virtual consultations as a result of COVID-19, we need to work out the best approach for overcoming language barriers in that setting too," she concluded.

Commenting on the findings of the two studies, Professor Sanjay Popat, from the Royal Marsden NHS Foundation Trust, London, UK, said that the results should be a wake-up call to all healthcare professionals involved in the care of patients with lung and other cancers to get processes in place to ensure effective communication.

"The statistics from the GLCC survey paint a bleak picture and at least 11% of patients not knowing their type of lung cancer is a very damning statistic. We want patients to be empowered to make decisions about how and where they want to be treated and that can only happen if we have good communication at all stages, with shared aims and goals," he said.

"If we can't get the basics right, it will be very difficult to ensure that patients understand the increasingly complex issues about their treatment options and possible side-effects, particularly the 'red flag' side-effects they need to tell us about immediately," he added.

Popat pointed out that the Dublin research underlines the need for experienced medical translators in an increasingly cosmopolitan society and the importance of 24/7 professional services, especially for patients being treated in hospital.

"The key thing is for everyone to know these translation services exist and to make use of them. Relying on family members to translate is not good practice. We need translators who know how to talk about difficult subjects such as prognosis and end of life care, and can help us understand cultural sensitivities so that we give information in an appropriate way," said Popat.

For patients with lung cancer facing communication or language barriers he highlighted the growing range of patient support groups specialising in providing information and support for specific types of the disease, such as ALK+ and EGFR mutation-positive non-small cell lung cancers.

"In many countries these specialist groups are becoming established to provide a lot of background information about these specific types of lung cancer and the kind of questions patients need to ask and what they should be expecting as part of their care. It all helps to ensure that communication about complex issues is as good as it can be in what is likely to be a very stressful situation for patients," Popat concluded.