Culture

The larynx is larger, more variable in size, and has undergone faster rates of evolution in primates than in carnivores, according to a study published August 11, 2020 in the open-access journal PLOS Biology by Daniel Bowling of Stanford University, W. Tecumseh Fitch of the University of Vienna, and colleagues.

The larynx is the main organ of vocal production, and a key target for evolutionary selection, particularly in those species that have a highly developed vocal communication systems. To shed light on the evolution of the larynx, Bowling and Fitch combined 3D computer models built from X-ray computed tomography scans with detailed digital measurements. They used these techniques to compare the larynx structure of 55 different mammalian species, representing a wide range of body sizes among primates and carnivores (from pygmy marmoset to gorilla and from dwarf mongoose to tiger). Carnivores were chosen as a comparable order of mammals with a similarly wide size range.

Using comparative methods known as phylogenetics, they showed that the larynx has evolved more rapidly in primates than in carnivores, resulting in a pattern of larger larynx size relative to body size, and greater variability in size. Acoustic vocalization data suggest that these differences are relevant to vocal communication. Moreover, larynx size is less tightly coupled to body size in primates than it is in carnivores, suggesting that the primate larynx has been freer to respond to fluctuations in evolutionary pressure. Taken together, the results imply fundamental differences between primates and carnivores in the balance of evolutionary forces that constrain larynx size, and highlight an evolutionary flexibility in primates that may help explain why we have developed complex and diverse uses of the vocal organ for communication.

USC researchers have found the likely order in which COVID-19 symptoms first appear: fever, cough, muscle pain, and then nausea, and/or vomiting, and diarrhea.

Knowing the order of COVID-19's symptoms may help patients seek care promptly or decide sooner than later to self-isolate, the scientists say. It also may help doctors rule out other illnesses, according to the study led by doctoral candidate Joseph Larsen and his colleagues with faculty advisors Peter Kuhn and James Hicks at the USC Michelson Center for Convergent Bioscience's Convergent Science Institute in Cancer.

Recognizing the order of symptoms also could help doctors plan how to treat patients, and perhaps intervene earlier in the disease.

"This order is especially important to know when we have overlapping cycles of illnesses like the flu that coincide with infections of COVID-19," said Kuhn, a USC professor of medicine, biomedical engineering, and aerospace and mechanical engineering. "Doctors can determine what steps to take to care for the patient, and they may prevent the patient's condition from worsening."

"Given that there are now better approaches to treatments for COVID-19, identifying patients earlier could reduce hospitalization time," said Larsen, the study's lead author.

Fever and cough are frequently associated with a variety of respiratory illnesses, including Middle East Respiratory Syndrome (MERS) and Severe Acute Respiratory Syndrome (SARS). But the timing and symptoms in the upper and lower gastrointestinal tract set COVID-19 apart.

"The upper GI tract (i.e., nausea/vomiting) seems to be affected before the lower GI tract (i.e., diarrhea) in COVID-19, which is the opposite from MERS and SARS," the scientists wrote.

The authors predicted the order of symptoms this spring from the rates of symptom incidence of more than 55,000 confirmed coronavirus cases in China, all of which were collected from Feb. 16-Feb. 24, 2020, by the World Health Organization. They also studied a dataset of nearly 1,100 cases collected from Dec. 11, 2019 through Jan. 29, 2020, by the China Medical Treatment Expert Group via the National Health Commission of China.

To compare the order of COVID-19 symptoms to influenza, the researchers examined data from 2,470 cases in North America, Europe and the Southern Hemisphere, which were reported to health authorities from 1994 to 1998.

The scientific findings were published Thursday in the journal Frontiers in Public Health.

"The order of the symptoms matter. Knowing that each illness progresses differently means that doctors can identify sooner whether someone likely has COVID-19, or another illness, which can help them make better treatment decisions," Larsen, the lead author, said.

Nylon manufacture could be revolutionised by the discovery that bacteria can make a key chemical involved in the process, without emitting harmful greenhouse gases.

Scientists have developed a sustainable method of making one of the most valuable industrial chemicals in the world - known as adipic acid - which is a key component of the material.

More than two million tonnes of the versatile fabric - used to make clothing, furniture and parachutes - is produced globally each year, with a market value of around £5 billion.

Industrial production of adipic acid relies on fossil fuels and produces large amounts of nitrous oxide - a greenhouse gas three hundred times more potent than carbon dioxide. A sustainable production method is urgently required to reduce the damage caused to the environment, the team says.

Scientists from the University of Edinburgh altered the genetic code of the common bacteria E.coli in the lab. The modified cells were grown in liquid solutions containing a naturally occurring chemical, called guaiacol, which is the main component of a compound that gives plants their shape.

Following a 24-hour incubation period, the modified bacteria transformed the guaiacol into adipic acid, without producing nitrous oxide.

The environmentally friendly approach could be scaled up to make adipic acid on an industrial scale, researchers say.

The study is published in ACS Synthetic Biology. It was funded by the Carnegie Trust and UK Research and Innovation.

Lead author Jack Suitor, a PhD student in the University of Edinburgh's School of Biological Sciences, said the team is continually exploring new ways of using bacteria to produce chemicals.

He said: "I am really excited by these results. It is the first time adipic acid has been made directly from guaiacol, which is one of the largest untapped renewable resources on the planet. This could entirely change how nylon is made."

Dr Stephen Wallace, Principle Investigator of the study, and a UKRI Future Leaders Fellow suggested microbes could help solve many other problems facing society.

He said: "If bacteria can be programmed to help make nylon from plant waste - something that cannot be achieved using traditional chemical methods - we must ask ourselves what else they could do, and where the limits lie. We are all familiar with the use of microbes to ferment food and beer - now we can ferment materials and medicines. The possibilities of this approach to create a sustainable future are staggering."

OAK BROOK, Ill. - There was a higher incidence and severity of physical intimate partner violence (IPV) among patients seen at a large, academic medical center in the U.S. during the COVID-19 pandemic compared with the prior three years, according to a new study published in Radiology.

"Our study showed a higher incidence of physical IPV, both in absolute numbers and proportion, with more severe injuries despite fewer patients reporting IPV," said Bharti Khurana, M.D., principal investigator and director of the Trauma Imaging Research and Innovation Center at Brigham and Women's Hospital in Boston, Massachusetts. "This indicates that victims are reporting to health care facilities in the late stages of the abuse cycle. Fear of contracting infection and closure of ambulatory sites might be preventing victims of mild physical or emotional abuse from seeking help compared to the pre-pandemic era."

Social distancing has proven to be effective for controlling the spread of coronavirus but with negative socioeconomic and psychological impacts. Service-oriented economies have seen increased unemployment and a higher incidence of substance and alcohol abuse and mental health disorders.

Since the outbreak of COVID-19, reports of IPV have increased worldwide during mandatory "lockdowns" to curb the spread of the virus.

Dr. Khurana and colleagues set out to assess the incidence, pattern and severity of injuries related to IPV at Brigham and Women's Hospital during COVID-19 pandemic. The demographics, clinical presentation, injuries and radiological findings of patients reporting physical abuse arising from IPV between March 11 and May 3, 2020, were compared with the same period over the past three years.

Data from 26 physical IPV victims from 2020 (37+/-13 years, 25 women) were evaluated and compared with 42 physical IPV victims (41+/-15 years, 40 women) from 2017 to 2019. While the overall number of patients reporting IPV was lower, the incidence of physical IPV was 1.8 times greater during the pandemic. Five victims of severe abuse were identified in 2020 (5/26=19%) compared to one each of the previous years.

The total number of deep injuries (injuries to deep internal organs) was 28 during 2020 versus 16 from 2017 to 2019. The number of deep injuries per victim was 1.1 during 2020 compared with 0.4 from 2017 to 2019. The incidence of high-risk abuse defined by mechanism (injuries due to strangulation, stab injuries, burns or use of weapons such as knives, guns and other objects that could inflict deep injuries) was 2 times greater. Patients with IPV during the COVID-19 pandemic were more likely to be ethnically white. Seventeen (65%) victims in 2020 were white, compared to 11 (26%) in the prior years.

"During the pandemic, victims experienced more injuries to the chest and abdomen compared to prior years," said coauthor Babina Gosangi, M.D., assistant professor of radiology at Yale New Haven Health in New Haven, Connecticut, and former emergency radiology fellow at Brigham and Women's Hospital. "For instance, one victim sustained multiple bilateral rib fractures with right pneumothorax and bilateral lung contusions--requiring hospital admission for more than 10 days--after she was repeatedly punched in the chest. Another victim was stabbed in the abdomen and had lacerations to the liver and kidney."

It is challenging to help IPV victims in the time of the pandemic when health care providers are overwhelmed by COVID-19 patients. In addition, alternative options for IPV victims to seek help have decreased. Many ambulatory clinics are no longer seeing as many patients in person due to the virus and are instead pivoting their services to virtual consultation. Telehealth visits limit the opportunity to visualize bruises or other signs of physical trauma and hamper the ability of the health care provider to gather nonverbal cues.

It may also be difficult for victims who are at home to report IPV, and health care providers may be omitting IPV screening questions altogether on these calls due to patient's limited privacy. Therefore, the role of radiologists in identifying victims of IPV through imaging exams has become crucial.

By recognizing high imaging utilization, location and imaging patterns specific to IPV, old injuries of different body parts, and injuries inconsistent to provided history, radiologists can identify victims of IPV even when the victims are not forthcoming.

Dr. Khurana, who is also assistant professor of radiology at Harvard Medical School in Boston, sees this as an opportunity for radiologists to use their expertise in providing patient-centered care and play a critical role in facilitating early intervention, preventing life-threatening injuries and saving lives by early identification of IPV victims.

"As health care providers, we are missing opportunities to identify victims early in the cycle during the pandemic," she said. "There is under-reporting by the victims, accentuated due to fear of seeking care due to COVID-19. At the same time, IPV-related injuries may be getting overlooked or misinterpreted, as our frontline physicians are overwhelmed by a vast number of COVID-19 patients in the Emergency Department."

The researchers emphasize that radiologists and other health care providers should proactively participate in identifying IPV victims and reaching out to vulnerable communities as an essential service during the pandemic and other crisis situations.

BOSTON - Investigators led by a team at Massachusetts General Hospital (MGH) have made discoveries at the single cell level to uncover new details concerning mitochondrial diseases-- inherited disorders that interfere with energy production in the body and currently have no cure. The findings, which are published in the New England Journal of Medicine, could eventually benefit affected patients.

Mitochondrial diseases result from failure of mitochondria, specialized compartments within cells that contain their own DNA and produce the energy needed to sustain life. Inherited mutations in mitochondrial DNA (mtDNA) often cause these diseases, and affected patients' cells contain a mixture of mutant and nonmutant mtDNA--a phenomenon called heteroplasmy. The proportion of mutant mtDNA varies across patients and among tissues within a patient. Also, symptoms range from mild to severe and depend on which cells of the body are affected.

"It is generally accepted that the fraction of mutant heteroplasmy is what determines whether or not a tissue will exhibit disease. To better understand heteroplasmic dynamics, we applied a brand new genomics technology--with single cell resolution--in which we could simultaneously determine the cell type and the fraction of mutant heteroplasmy in thousands of individual blood cells," said senior author Vamsi K. Mootha, MD, investigator in the Department of Molecular Biology at MGH.

The researchers examined mtDNA within different blood cell types from 9 individuals with MELAS, one of the most common forms of mtDNA disease associated with brain dysfunction and stroke-like episodes, with a wide range of severity across patients.

"What makes this study unique is that it is, to our knowledge, the first time anyone has been able to quantify the percentage of disease-causing mitochondrial DNA mutations in thousands of individual cells of different types from the same patient, as well as in multiple patients with inherited mitochondrial disease," said lead author Melissa A. Walker, MD, PhD, an investigator in the Department of Neurology at MGH.

The analysis revealed especially low levels of heteroplasmy in T cells, which play important roles in killing infected cells, activating other immune cells, and regulating immune responses.

"Our observations suggest that certain cell lineages within our body may have a process by which to guard against problematic mtDNA mutations, which is a potentially very exciting finding," said Walker.

Additional studies are needed to determine whether differences in heteroplasmy across immune cell types affect the cells' function, and whether assessing such heteroplasmy may help clinicians diagnose and monitor mitochondrial diseases. "Our long-term vision is that single cell genomics may lead to improved blood tests for monitoring the progression of these diseases," said Mootha.

In addition, understanding the determinants of reduced T-cell heteroplasmy may motivate new therapeutic strategies for mitochondrial diseases, which currently lack any FDA-approved treatments.

Mootha added that mtDNA mutations also occur spontaneously during normal aging. "Although our work focused on rare, inherited diseases, it has potential implications for the heteroplasmic dynamics of aging as well," he said.

Progress against DIPG, a fatal childhood brain tumor, is usually a game of inches. Studies that hint at even small gains are cause for celebration.

That's why researchers at the University of Michigan and their collaborators are excited about discoveries that point toward a new potential treatment approach -- one that significantly lengthened survival times in two mouse models of DIPG.

The team's findings, which appear in the journal Cancer Cell, suggest that simultaneously targeting two energy-production pathways within the cancer cells could help overcome the effects of a cancer-causing mutation that is one of the hallmarks of DIPG, or diffuse intrinsic pontine glioma, and similar tumors.

"DIPGs have a characteristic, epigenetic histone mutation -- that is, a mutation in the spool that DNA wraps around, and which can affect gene expression," says the study's senior author Sriram Venneti, M.D., Ph.D., a neuropathologist and researcher at the U-M Rogel Cancer Center and Chad Carr Pediatric Brain Tumor Center. "It's not clear exactly how this mutation causes cancer, but it's associated with poor outcomes, which implies these mutations are aggressively driving the biology of these tumors."

An epigenetic change is one that affects how a gene gets used without changing the underlying DNA sequence -- similar to the way a playlist of songs can be altered without changing the songs themselves.

"What we discovered, unexpectedly, is that this mutation specifically increases activity in two metabolic pathways in the cell, and that these pathways also directly influence the epigenetic changes within the cell," Venneti says. "So the question was: Can we use metabolic drugs to interrupt these energy production pathways within the cancer cells and at the same time modify the cells' epigenome in a productive way?"

The result in two different mouse models of DIPG was a resounding yes.

Inhibiting each of the two metabolic pathways individually provided a small increase in how long the mice survived, while targeting both pathways at the same time caused the mice to live much longer.

In one model used in the study, DIPG is always fatal. When the two experimental compounds were given, however, 60% of the mice were still alive, when the experiments were ended.

"Treatments for DIPG are desperately needed. So, while these are still early stage, pre-clinical results, we are excited about continuing to develop this new strategy toward human clinical trials," Venneti says.

DIPG is usually diagnosed in children between the ages of 5 and 10, though it can develop at any age, including rare cases in adults. These tumors start in the brainstem, which makes them nearly impossible to remove surgically. In 2015, Chad Carr, the grandson of former U-M football coach Lloyd Carr, died at age 5 after being diagnosed with the disease 14 months earlier.

"The Chad Carr Pediatric Brain Tumor Center was started in 2018 and has placed the University of Michigan as one of the leading centers for DIPG research and patient care. We could not have performed this research without their strong support and critical funding from the Chad Tough Foundation," Venneti says.

Both of the compounds used in the study -- one of which was developed by the pharmaceutical company AbbVie and the other by Johns Hopkins University -- are able to penetrate the blood-brain barrier, which is critical for treating brain tumors, Venneti adds.

"The barrier is there for a reason," he says. "You don't want toxins to be able to reach your brain. The challenge in developing drugs against brain cancer is that you need the drugs to be able to cross through this barrier and attack the tumor cells. We were fortunate that both of the study compounds can do so."

The study also uncovered new information about the biology of DIPGs and related tumors through the analysis of cancer cells and imaging scans from DIPG patients. Along with shedding new light on the energy cycles of the cancer cells, researchers discovered why two different types of mutations -- one seen in children with DIPG and the other observed in adult brain tumors -- are mutually exclusive.

"We found that these two mutations use the same pathways, but in opposite ways, which explains why they can't occur at the same time," Venneti says.

Continuing to develop a better understanding of the underlying tumor biology will help researchers to develop and refine new treatment strategies, he notes.

Adopting a third-person, observer point of view when recalling your past activates different parts of your brain than recalling a memory seen through your own eyes, according to a new paper.

"Our perspective when we remember changes which brain regions support memory and how these brain regions interact together," explained Peggy St Jacques, assistant professor in the Faculty of Science'sDepartment of Psychology and co-author on the paper.

Specifically, the results show that recalling memories from an observer-like perspective, instead of through your own eyes, leads to greater interaction between the anterior hippocampus and the posterior medial network.

"These findings contribute to a growing body of research that show that retrieving memories is an active process that can bias and even distort our memories," added St Jacques.

"Adopting an observer-like perspective involves viewing the past in a novel way, which requires greater interaction among brain regions that support our ability to recall the details of a memory and to recreate mental images in our mind's eye."

Adopting an observer-like perspective may also serve a therapeutic purpose, explained St Jacques. "This may be an effective way of dealing with troubling memories by viewing the past from a distance and reducing the intensity of the emotions we feel."

This work builds on St Jacques' previous research on visual perspective in memory, which found that the perspective from which we recall a memory can influence how we remember them over time.

A recent paper published in The Economic Journal indicates that, in families with disabled children, the second born child is more adversely affected cognitively than the first-born child.

Brothers and sisters share a unique bond. They typically grow up in the same household, with the same parents and similar genetics, and experience life events together. Siblings have important influences on each other's lives. Siblings might teach each other directly; they might also model behaviors. But they also share limited parental resources such as time, attention, and money directed towards one child might be time, attention, and money diverted from another.

The researchers, analyzing data from Florida and Denmark, studied how adverse health shocks to one child could propagate to their siblings. Specifically, they examined the effect of having a younger sibling with a disability on test scores of older children, measured when they were in elementary and middle school.

Sibling disability is significant, as millions of families have at least one disabled child. In 2012-13, for instance, in the United States alone over 6.4 million children aged 3 to 21 (12.9% of all students) were supported under Part B of the Individuals with Disabilities Education Act. The Florida analysis considers disabilities requiring special accommodations in school, while the Danish analysis is based on disabilities recorded in medical registries, so the two sites estimate the effects of fundamentally different types of disabilities. In Florida, the most common early childhood disabilities considered are speech impairment (48%), developmental delay (21%), and language impairment (17%). In Denmark, for the same age range, the most common disabilities considered are congenital malformations and deformations of the musculoskeletal system (20%), congenital malformations of the circulatory system (10%), and congenital malformations of genital organs (9%).

In order to causally identify sibling spillovers resulting from a younger child's disability, the researchers considered families with three or more children where a health shock (disability) occurred in the case of the third child. Within a family, the first- and second-born children face differential exposure to the affected third sibling. This differential exposure is related to the relative ordering of the two children; earlier-born children had more time in the family without the presence of the disabled third child, and are thus less exposed. The researchers did not find differential effect of exposure on birth and early postnatal outcomes for these children, outcomes that were measured prior to the arrival of third born child, disabled or not.

Despite the differences in settings and disabilities considered across Florida and Denmark, the researchers found evidence in both places consistent with there being a sibling spillover. They found that the second-born child in a family had worse outcomes (test scores in Florida, grade point average in Denmark) than did their older sibling when the third-born sibling was disabled, relative to the case in which the third-born sibling was not disabled. The magnitude of these differences is significant; for example, in Florida it is about half of the observed relationship between an extra year of maternal education and children's test scores. These results are concentrated in cases in which the third child's disability is observed early - and therefore, presumably, more likely to affect older siblings in early childhood. Furthermore, the results are driven by physical disabilities - which are likely to be more visible early and require more parental time and attention - rather than cognitive or behavioral disabilities.

"I think we all believe that individuals are affected by their siblings when they are growing up--either directly through their interactions with each other or indirectly through the allocation of parental resources such as money, time, and attention. However, it is very difficult to isolate empirically, because there are so many things simultaneously happening in the family that might also affect these children's outcomes," said the paper's lead author, Sandra Black. "It is exciting that we are able to make progress on this front and document the importance of siblings."

CLEVELAND--Luis Ortiz-Rodríguez grew up on the beaches of Puerto Rico--surfing, swimming and running in the hot sand--and swears he had never put on sunblock a day in his life.
 

Then the day came when he peered through an ultrafast laser spectrometer at the College of Arts & Sciences at Case Western Reserve University and observed and recorded pre-cancerous lesions forming on the DNA within three picoseconds after exposure to ultraviolet light.
 

That's picosecond, as in one trillionth of a second.
 

"It's amazing how quickly this happens," said Ortiz-Rodríguez, a PhD researcher in chemistry at Case Western Reserve University. "And it's true, when I was younger, I was always running shirtless on the beach or surfing and I thought sunblock was just for old people. Not anymore."
 

New research by Ortiz-Rodríguez and mentor Carlos Crespo, a professor and lead researcher in the The Crespo Group lab, reveals for perhaps the first time how quickly certain pre-cancerous lesions can form on the DNA of our skin when exposed to sunlight.
 

"That's important," Ortiz-Rodríguez said, "because we need and want to know how fast the mutations can form in the DNA, so that maybe researchers can find a better way to prevent skin cancer at a cellular level."

The 6-4 photo adducts mutation

Their research, recently published in the journal Nature Communications, shows how they've detected fast-forming mutations--called "DNA (6-4) photo adducts" by scientists." Photo adducts are lesions formed by a light-induced reaction in cellular DNA, which can lead to skin cancers. (The numbers 6-4 refers to the location of the relevant segment of DNA, see illustration at bottom).

Previous research published in Science by Crespo and collaborators has shown the other primary photo adduct linked to skin cancers, the thymine-thymine cyclobutane photo adduct, forms in less than 1 picosecond. But this work is the first to defined so precisely the formation mechanism of the 6-4 photo adduct.
 

They believe their findings will provide a stepping-stone toward a fuller understanding of how skin cancerous lesions actually form--a discovery that Crespo believes could have a big impact on the economics of treating and preventing skin cancer.
 

Skin cancer costs

With over 5 million cases diagnosed in the United States each year, skin cancer is America's most common cancer, according to the Skin Cancer Foundation, and the annual cost of treating skin cancers in the United States is about $8.1 billion.

The research also affirms that while most of us don't worry about the occasional sunburn because the discomfort fades in a few days, the longer-term damage stays hidden for decades, Crespo said.
 

"You're forming these mutations in your skin every second that you are exposed to sunlight, but enzymes in your cells repair more than 99% of them," Crespo said. "The problem is the less than 1% that remains un-repaired because they can accumulate in your body, often until you're much older and then they can lead to skin cancers."

The search for these precursors to skin cancer has actually been going on in earnest since the late 1960s, Crespo said. Until now, the timescale of its formation and the reactive-state precursor had eluded researchers around the world.
 

"Even though it is well established that formation of the 6-4 photo adduct is an initial pre-cancer lesion leading to skin cancer, we didn't fully understand the mechanistic aspects of it formation, so our paper provides important information in the characterization and understanding of these reactions," Crespo said. "Understanding the chemical processes could help us design better sunblock or maybe avoid the damage to the DNA before it occurs."
 

A Princeton team has developed a class of light-switchable, highly adaptable molecular tools with new capabilities to control cellular activities. The antibody-like proteins, called OptoBinders, allow researchers to rapidly control processes inside and outside of cells by directing their localization, with potential applications including protein purification, the improved production of biofuels, and new types of targeted cancer therapies.

In a pair of papers published Aug. 13 in Nature Communications, the researchers describe the creation of OptoBinders that can specifically latch onto a variety of proteins both inside and outside of cells. OptoBinders can bind or release their targets in response to blue light. The team reported that one type of OptoBinder changed its affinity for its target molecules up to 330-fold when shifted from dark to blue light conditions, while others showed a five-fold difference in binding affinity -- all of which could be useful to researchers seeking to understand and engineer the behaviors of cells.

Crucially, OptoBinders can target proteins that are naturally present in cells, and their binding is easily reversible by changing light conditions -- "a new capability that is not available to normal antibodies," said co-author José Avalos, an assistant professor of chemical and biological engineering and the Andlinger Center for Energy and the Environment. "The ability to let go [of a target protein] is actually very valuable for many applications," said Avalos, including engineering cells' metabolisms, purifying proteins or potentially making biotherapeutics.

The new technique is the latest in a collaboration between Avalos and Jared Toettcher, an assistant professor of molecular biology. Both joined the Princeton faculty in 2015, and soon began working together on new ways to apply optogenetics -- a set of techniques that introduce genes encoding light-responsive proteins to control cells' behaviors.

"We hope that this is going to be the beginning of the next era of optogenetics, opening the door to light-sensitive proteins that can interface with virtually any protein in biology, either inside or outside of cells," said Toettcher, the James A. Elkins, Jr. '41 Preceptor in Molecular Biology.

Avalos and his team hope to use OptoBinders to control the metabolisms of yeast and bacteria to improve the production of biofuels and other renewable chemicals, while Toettcher's lab is interested in the molecules' potential to control signaling pathways involved in cancer.

The two papers describe different types of light-switchable binders: opto-nanobodies and opto-monobodies. Nanobodies are derived from the antibodies of camelids, the family of animals that includes camels, llamas and alpacas, which produce some antibodies that are smaller (hence the name nanobody) and simpler in structure than those of humans or other animals.

Nanobodies' small size makes them more adaptable and easier to work with than traditional antibodies; they recently received attention for their potential as a COVID-19 therapy. Monobodies, on the other hand, are engineered pieces of human fibronectin, a large protein that forms part of the matrix between cells.

"These papers go hand in hand," said Avalos. "The opto-nanobodies take advantage of the immune systems of these animals, and the monobodies have the advantage of being synthetic, which gives us opportunities to further engineer them in different ways."

The two types of OptoBinders both incorporate a light-sensitive domain from a protein found in oat plants.

"When you turn the light on and off, these tools bind and release their target almost immediately, so that brings another level of control" that was not previously possible, said co-author César Carrasco-López, an associate research scholar in Avalos' lab. "Whenever you are analyzing things as complex as metabolism, you need tools that allow you to control these processes in a complex way in order to understand what is happening."

In principle, OptoBinders could be engineered to target any protein found in a cell. With most existing optogenetic systems, "you always had to genetically manipulate your target protein in a cell for each particular application," said co-author Agnieszka Gil, a postdoctoral research fellow in Toettcher's lab. "We wanted to develop an optogenetic binder that did not depend on additional genetic manipulation of the target protein."

In a proof of principle, the researchers created an opto-nanobody that binds to actin, a major component of the cytoskeleton that allows cells to move, divide and respond to their environment. The opto-nanobody strongly bound to actin in the dark, but released its hold within two minutes in the presence of blue light. Actin proteins normally join together to form filaments just inside the cell membrane and networks of stress fibers that traverse the cell. In the dark, the opto-nanobody against actin binds to these fibers; in the light, these binding interactions are disrupted, causing the opto-nanobody to scatter throughout the cell. The researchers could even manipulate binding interactions on just one side of a cell -- a level of localized control that opens new possibilities for cell biology research.

OptoBinders stand to unlock scores of innovative, previously inaccessible uses in cell biology and biotechnology, said Andreas Möglich, a professor of biochemistry at the University of Bayreuth in Germany who was not involved in the studies. But, Möglich said, "there is much more to the research" because the design strategy can be readily translated to other molecules, paving the way to an even wider repertoire of customized, light-sensitive binders.

"The impressive results mark a significant advance," he said.

"Future applications will depend on being able to generate more OptoBinders" against a variety of target proteins, said Carrasco-López. "We are going to try to generate a platform so we can select OptoBinders against different targets" using a standardized, high-throughput protocol, he said, adding that this is among the first priorities for the team as they resume their experiments after lab research was halted this spring due to COVID-19.

Beyond applications that involve manipulating cell metabolism for microbial chemical production, Avalos said, OptoBinders could someday be used to design biomaterials whose properties can be changed by light.

The technology also holds promise as way to reduce side effects of drugs by focusing their action to a specific site in the body or adjusting dosages in real time, said Toettcher, who noted that applying light inside the body would require a device such as an implant. "There aren't many ways to do spatial targeting with normal pharmacology or other techniques, so having that kind of capability for antibodies and therapeutic binders would be a really cool thing," he said. "We think of this as a sea change in what sorts of processes can be placed under optogenetic control."

WASHINGTON (August 13, 2020)-- An online COVID-19 symptom tracking tool developed by researchers at Georgetown University Medical Center ensures a person's confidentiality while being able to actively monitor their symptoms. The tool is not proprietary and can be used by entities that are not able to develop their own tracking systems.

Identifying and monitoring people infected with COVID-19, or exposed to people with infection, is critical to preventing widespread transmission of the disease. Details of the COVID19 Symptom Tracker and a pilot study were published August 13, 2020, in the Journal of Medical Information Research (JMIR).

"One of the major impediments to tracking people with, or at risk of, COVID-19 has been an assurance of privacy and confidentiality," says infectious disease expert Seble G. Kassaye, MD, MS, lead author and associate professor of medicine at Georgetown University Medical Center. "Our online system provides a method for efficient, active monitoring of large numbers of individuals under quarantine or home isolation, while maintaining privacy."

The Georgetown internet tool assigns a unique identifier as people enter their symptoms and other relevant demographic data. One function in the system allows institutions to generate reports about items on which people can act, such as symptoms that might require medical attention. Additionally, people using the system are provided with information and links to Centers for Disease Control and Prevention COVID-19 recommendations and instructions for how people with symptoms should seek care.

Development of the system was rapid -- it took five days to design. The joint project included Georgetown University's J.C. Smart, PhD, chief scientist of AvesTerra, a knowledge management environment that supports data integration and synthesis to identify actionable events and maintain privacy, and Georgetown's vice president for research and chief technology officer, Spiros Dimolitsas, PhD.

"We knew that time was of the essence and the challenges of traditional contact tracing became very clear to us based on one of our first patients who had over 500 exposures," says Kassaye. "This was what motivated us to work on this, essentially day and night."

The tool launched on March 20, followed by initial testing of the system with the voluntary participation of 48 Georgetown University School of Medicine students or their social contacts. Participants were asked to enter data twice daily for three days between March 31 and April 5, 2020.

"The lack of identifying data being collected in the system should reassure individual users and alleviate personal inhibitions that appear to be the Achille's heel of other digital contact tracing apps that require identifying information," says Kassaye. She also noted that this system could be used by health-related organizations during the re-opening of business to provide reassurance to their users that the enterprise is actively, rather than passively, monitoring its staff.

Feedback from healthcare groups using the platform led to the release of a Spanish language version. As the data currently needs to be entered through the website, development of an app for cellphone use could greatly enhance the usability of the tool, said the investigators. For places where internet access is problematic, the researchers are also pursuing development of a voice activated version.

The tracker can be view at http://www.covidgu.org.

WASHINGTON -- Researchers have designed an off-grid, low-cost modular energy source that can efficiently produce power at night. The system uses commercially available technology and could eventually help meet the need for nighttime lighting in urban areas or provide lighting in developing countries.

Although solar power brings many benefits, its use depends heavily on the distribution of sunlight, which can be limited in many locations and is completely unavailable at night. Systems that store energy produced during the day are typically expensive, thus driving up the cost of using solar power.

To find a less-expensive alternative, researchers led by Shanhui Fan from Stanford University looked to radiative cooling. This approach uses the temperature difference resulting from heat absorbed from the surrounding air and the radiant cooling effect of cold space to generate electricity.

In The Optical Society (OSA) journal Optics Express, the researchers theoretically demonstrate an optimized radiative cooling approach that can generate 2.2 Watts per square meter with a rooftop device that doesn't require a battery or any external energy. This is about 120 times the amount of energy that has been experimentally demonstrated and enough to power modular sensors such as ones used in security or environmental applications.

"We are working to develop high-performance, sustainable lighting generation that can provide everyone - including those in developing and rural areas - access to reliable and sustainable low cost lighting energy sources," said Lingling Fan, first author of the paper. "A modular energy source could also power off-grid sensors used in a variety of applications and be used to convert waste heat from automobiles into usable power."

Maximizing power generation

One of the most efficient ways to generate electricity using radiative cooling is to use a thermoelectric power generator. These devices use thermoelectric materials to generate power by converting the temperature differences between a heat source and the device's cool side, or radiative cooler, into an electric voltage.

In the new work, the researchers optimized each step of thermoelectric power generation to maximize nighttime power generation from a device that would be used on a rooftop. They improved the energy harvesting so that more heat flows into the system from the surrounding air and incorporate new commercially available thermoelectric materials that enhance how well that energy is used by the device. They also calculated that a thermoelectric power generator covering one square meter of a rooftop could achieve the best trade-off between heat loss and thermoelectric conversion.

"One of the most important innovations was designing a selective emitter that is attached to the cool side of the device," said Wei Li, a member of the research team. "This optimizes the radiative cooling process so that the power generator can more efficiently get rid of excessive heat."

The researchers demonstrated the new approach by using computer modeling to simulate a system with realistic physical parameters. The models reproduced previous experimental results faithfully and revealed that the optimized system designed by the researchers could come close to what has been calculated as the maximum efficiency using thermoelectric conversion.

In addition to carrying out experiments, the researchers are also examining optimal designs for operating the system during the day, in addition to nighttime, which could expand the practical applications of the system.

University of Toronto Engineering researchers have developed a new method of injecting healthy cells into damaged eyes. The technique could point the way toward new treatments with the potential to reverse forms of vision loss that are currently incurable.

Around the world, millions of people live with vision loss due to conditions such as age-related macular degeneration (AMD) or retinitis pigmentosa. Both are caused by the death of cells in the retina, at the back of the eye.

"The cells that are responsible for vision are the photoreceptors, which have an intimate relationship with another type of cell known as retinal pigmented epithelium (RPE) cells," says Professor Molly Shoichet.

"In AMD, the RPE die first, and this then causes the photoreceptors to die."

Many researchers have experimented with treatments based on injecting healthy photoreceptors or RPE cells into the eye to replace the dead cells. But integrating the new cells into the existing tissue is a major challenge, and most injected cells end up dying as well.

Shoichet and her team are experts in using engineered biomaterials known as hydrogels to promote the survival of newly injected cells after transplantation. The hydrogels ensure an even distribution of cells, reduce inflammation and promote tissue healing in the critical early days post-injection. Eventually, they degrade naturally, leaving the healthy cells behind.

In 2015, the team used hydrogels to inject healthy photoreceptor cells into damaged retinas in a mouse model. While the team observed some vision repair, the benefits were limited, so they began to think more carefully about the relationships between RPE cells and photoreceptors.

"RPE and photoreceptors are considered as one functional unit -- if one cell type dies, then the other one will too," says Shoichet. "We wondered if co-delivery of both cell types would have a bigger impact on vision restoration."

As with photoreceptors, many groups had tried implanting RPE cells on their own, but nobody had ever integrated both cell types into a single treatment. Once again, the hydrogels pointed to a solution.

"What other groups have typically done is either inject photoreceptors in a saline solution, which often results in cells clustering together, or surgically implant a layer of RPE cells usually grown on a polymer film," says Shoichet.

"Our hydrogel is viscous enough to ensure a good distribution of both cell types in the syringe, yet it also has important shear-thinning properties to facilitate injection through the very fine needle required for this operation," adds Shoichet. "The combination of these properties opened up a new strategy for successful delivery of multiple cells."

The team tested co-injection in a degenerative mouse model resembling AMD. In a paper recently published in the journal Biomaterials, they report that mice who received the co-injection regained about 10 percent of their normal visual acuity. Those who received either cell type on its own showed little to no improvement.

Co-injected mice were also more active in dark chambers than light ones, showing that these nocturnal animals could once again distinguish light and shadow.

"I still remember the long days of behavioural testing," says Nick Mitrousis, Shoichet's former PhD student and lead author of the paper, now a postdoctoral fellow at the University of Chicago.

"We designed the experiment so that I wouldn't know which mice had received the treatment and which received a placebo. When some of the mice started responding, I kept vacillating between optimism that the experiment might have actually worked, and worry that the recovering mice might just be split between the different treatment groups."

The worries were unfounded: it turned out that the co-injection treatment really had an effect. But both Mitrousis and Shoichet caution that there is a very long road between these preliminary results and a trial that could eventually find its way into the clinic.

"First, we need to demonstrate the benefit of this strategy in multiple animal models," says Shoichet. "We'll also need a source of human photoreceptor cells and a way to further improve cell survival, both of which we're working on. Still, we are very excited by these data and always open to collaboration to take the research further."

PROVIDENCE, R.I. [Brown University] -- As levels of atmospheric carbon dioxide continue to climb, scientists are looking for new ways of breaking down CO2 molecules to make useful carbon-based fuels, chemicals and other products. Now, a team of Brown University researchers has found a way to fine-tune a copper catalyst to produce complex hydrocarbons -- known as C2-plus products -- from CO2 with remarkable efficiency.

In a study published in Nature Communications, the researchers report a catalyst that can produce C2-plus compounds with up to 72% faradaic efficiency (a measure of how efficiently electrical energy is used to convert carbon dioxide into chemical reaction products). That's far better than the reported efficiencies of other catalysts for C2-plus reactions, the researchers say. And the preparation process can be scaled up to an industrial level fairly easily, which gives the new catalyst potential for use in large-scale CO2 recycling efforts.

"There had been reports in the literature of all kinds of different treatments for copper that could produce these C2-plus with a range of different efficiencies," said Tayhas Palmore, the a professor of engineering at Brown who co-authored the paper with Ph.D. student Taehee Kim. "What Taehee did was a set of experiments to unravel what each of these treatment steps was actually doing to the catalyst in terms of reactivity, which pointed the way to optimizing a catalyst for these multi-carbon compounds."

There have been great strides in recent years in developing copper catalysts that could make single-carbon molecules, Palmore says. For example, Palmore and her team at Brown recently developed a copper foam catalyst that can produce formic acid efficiently, an important single-carbon commodity chemical. But interest is increasing in reactions that can produce C2-plus products.

"Ultimately, everyone seeks to increase the number of carbons in the product to the point of producing higher carbon fuels and chemicals," Palmore said.

There had been evidence from prior research that halogenation of copper -- a reaction that coats a copper surface with atoms of chlorine, bromine or iodine in the presence of an electrical potential -- could increase a catalyst's selectivity of C2-plus products. Kim experimented with a variety of different halogenation methods, zeroing in on which halogen elements and which electrical potentials yielded catalysts with the best performance in CO2-to-C2-plus reactions. He found that the optimal preparations could yield faradaic efficiencies of between 70.7% and 72.6%, far higher than any other copper catalyst.

The research helps to reveal the attributes that make a copper catalyst good for C2-plus products. The preparations with the highest efficiencies had a large number of surface defects -- tiny cracks and crevices in the halogenated surface -- that are critical for carbon-carbon coupling reactions. These defect sites appear to be key to the catalysts' high selectivity toward ethylene, a C2-plus product that can be polymerized and used to make plastics.

Ultimately, such a catalyst will aid in large-scale recycling of CO2. The idea is to capture CO2 produced by industrial facilities like power plants, cement manufacturing or directly from air, and convert it into other useful carbon compounds. That requires an efficient catalyst that is easy to produce and regenerate, and inexpensive enough to operate on an industrial scale. This new catalyst is a promising candidate, the researchers say.

"We were working with lab-scale catalysts for our experiments, but you could produce a catalyst of virtually any size using the method developed," Palmore said.

Sugars and fats are the primary fuels that power every cell, tissue and organ. For most cells, sugar is the energy source of choice, but when nutrients are scarce, such as during starvation or extreme exertion, cells will switch to breaking down fats instead.

The mechanisms for how cells rewire their metabolism in response to changes in resource availability are not yet fully understood, but new research reveals a surprising consequence when one such mechanism is turned off: an increased capacity for endurance exercise.

In a study published in the Aug. 4 issue of Cell Metabolism, Harvard Medical School researchers identified a critical role of the enzyme, prolyl hydroxylase 3 (PHD3), in sensing nutrient availability and regulating the ability of muscle cells to break down fats. When nutrients are abundant, PHD3 acts as a brake that inhibits unnecessary fat metabolism. This brake is released when fuel is low and more energy is needed, such as during exercise.

Remarkably, blocking PHD3 production in mice leads to dramatic improvements in certain measures of fitness, the research showed. Compared with their normal littermates, mice lacking the PHD3 enzyme ran 40 percent longer and 50 percent farther on treadmills and had higher VO2 max, a marker of aerobic endurance that measures the maximum oxygen uptake during exercise.

The findings shed light on a key mechanism for how cells metabolize fuels and offer clues toward a better understanding of muscle function and fitness, the authors said.

"Our results suggest that PHD3 inhibition in whole body or skeletal muscle is beneficial for fitness in terms of endurance exercise capacity, running time and running distance," said senior study author Marcia Haigis, professor of cell biology in the Blavatnik Institute at HMS. "Understanding this pathway and how our cells metabolize energy and fuels potentially has broad applications in biology, ranging from cancer control to exercise physiology."

However, further studies are needed to elucidate whether this pathway can be manipulated in humans to improve muscle function in disease settings, the authors said.

Haigis and colleagues set out to investigate the function of PHD3, an enzyme that they had found to play a role regulating fat metabolism in certain cancers in previous studies. Their work showed that, under normal conditions, PHD3 chemically modifies another enzyme, ACC2, which in turn prevents fatty acids from entering mitochondria to be broken down into energy.

In the current study, the researchers' experiments revealed that PHD3 and another enzyme called AMPK simultaneously control the activity of ACC2 to regulate fat metabolism, depending on energy availability.

In isolated mouse cells grown in sugar-rich conditions, the team found that PHD3 chemically modifies ACC2 to inhibit fat metabolism. Under low-sugar conditions, however, AMPK activates and places a different, opposing chemical modification on ACC2, which represses PHD3 activity and allows fatty acids to enter the mitochondria to be broken down for energy.

These observations were confirmed in live mice that were fasted to induce energy-deficient conditions. In fasted mice, the PHD3-dependent chemical modification to ACC2 was significantly reduced in skeletal and heart muscle, compared to fed mice. By contrast, the AMPK-dependent modification to ACC2 increased.

Longer and further

Next, the researchers explored the consequences when PHD3 activity was inhibited, using genetically modified mice that do not express PHD3. Because PHD3 is most highly expressed in skeletal muscle cells and AMPK has previously been shown to increase energy expenditure and exercise tolerance, the team carried out a series of endurance exercise experiments.

"The question we asked was if we knock out PHD3," Haigis said, "would that increase fat burning capacity and energy production and have a beneficial effect in skeletal muscle, which relies on energy for muscle function and exercise capacity?"

To investigate, the team trained young, PHD3-deficient mice to run on an inclined treadmill. They found that these mice ran significantly longer and further before reaching the point of exhaustion, compared to mice with normal PHD3. These PHD3-deficient mice also had higher oxygen consumption rates, as reflected by increased VO2 and VO2 max.

After the endurance exercise, the muscles of PHD3-deficient mice had increased rates of fat metabolism and an altered fatty acid composition and metabolic profile. The PHD3-dependent modification to ACC2 was nearly undetectable, but the AMPK-dependent modification increased, suggesting that changes to fat metabolism play a role in improving exercise capacity.

These observations held true in mice genetically modified to specifically prevent PHD3 production in skeletal muscle, demonstrating that PHD3 loss in muscle tissues is sufficient to boost exercise capacity, according to the authors.

"It was exciting to see this big, dramatic effect on exercise capacity, which could be recapitulated with a muscle-specific PHD3 knockout," Haigis said. "The effect of PHD3 loss was very robust and reproducible."

The research team also performed a series of molecular analyses to detail the precise molecular interactions that allow PHD3 to modify ACC2, as well as how its activity is repressed by AMPK.

The study results suggest a new potential approach for enhancing exercise performance by inhibiting PHD3. While the findings are intriguing, the authors note that further studies are needed to better understand precisely how blocking PHD3 causes a beneficial effect on exercise capacity.

In addition, Haigis and colleagues found in previous studies that in certain cancers, such as some forms of leukemia, mutated cells express significantly lower levels of PHD3 and consume fats to fuel aberrant growth and proliferation. Efforts to control this pathway as a potential strategy for treating such cancers may help inform research in other areas, such as muscle disorders.

It remains unclear whether there are any negative effects of PHD3 loss. To know whether PHD3 can be manipulated in humans--for performance enhancement in athletic activities or as a treatment for certain diseases --will require additional studies in a variety of contexts, the authors said.

It also remains unclear if PHD3 loss triggers other changes, such as weight loss, blood sugar and other metabolic markers, which are now being explored by the team.

"A better understanding of these processes and the mechanisms underlying PHD3 function could someday help unlock new applications in humans, such as novel strategies for treating muscle disorders," Haigis said.

Additional authors on the study include Haejin Yoon, Jessica Spinelli, Elma Zaganjor, Samantha Wong, Natalie German, Elizabeth Randall, Afsah Dean, Allen Clermont, Joao Paulo, Daniel Garcia, Hao Li, Olivia Rombold, Nathalie Agar, Laurie Goodyear, Reuben Shaw, Steven Gygi and Johan Auwerx.