Publisher Health

DNA can mimic protein functions by folding into elaborate, three-dimensional structures, according to a study from researchers at Weill Cornell Medicine and the National Heart, Lung, and Blood Institute, part of the National Institutes of Health.
In the study, published June 21 in Nature, the researchers used high-resolution imaging techniques to reveal the novel and complex structure of a DNA molecule they created that mimics the activity of a protein called green fluorescent protein (GFP). GFP, which was derived from jellyfish, has become an important laboratory tool, functioning as a fluorescent tag or beacon in cells.
The findings advance the science of how DNA can be made to fold into complex shapes, and will help researchers build such DNA molecules for a variety of laboratory and clinical applications. An all-DNA fluorescent tag that mimics GFP, for example, would often be ideal for labeling targeted pieces of DNA in biological studies and in diagnostic test kits, and would be relatively inexpensive to make.
“These findings really change our understanding of what we can do with DNA,” said study co- author Dr. Samie Jaffrey, Greenberg-Starr Professor of Pharmacology and a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine.
DNA in nature exists mostly in a double-stranded, “twisted ladder” or “helical” form, and serves as a relatively stable store of genetic information. All of the other complex biological processes in cells are done by other types of molecules, especially proteins.
Last year, Dr. Jaffrey and colleagues reported discovering one such molecule: a single-stranded DNA that folds in a way that allows it to mimic the activity of GFP. The DNA molecule, which Dr. Jaffrey dubbed “lettuce” for the color of its fluorescent emissions, works by binding to another small organic molecule, a potentially fluorescent “fluorophore” similar to the one at the heart of GFP, and squeezing it in a way that activates its ability to fluoresce. The researchers demonstrated the lettuce-fluorophore combination as a fluorescent tag for the rapid detection of SARS-CoV-2, the cause of COVID-19.
Dr. Jaffrey and his team discovered lettuce by making many single-stranded DNAs and screening for those with the desired fluorophore-activating ability. But they didn’t know what structure lettuce used to acquire this ability. To determine that structure, they turned — in the new study — to their long-time collaborator, NHLBI senior investigator Dr. Adrian R. Ferré-D’Amaré.
In the research led by Dr. Luiz Passalacqua, a research fellow at Dr. Ferré-D’Amaré’s team, advanced structural imaging techniques were used, including cryo-electron microscopy, to resolve the structure of lettuce at atomic-scale resolution. They found that it folds into a shape that has at its center a four-way junction of DNA, of a type never seen before, enclosing the fluorophore in a way that activates it. They also observed that lettuce’s foldings are held together with bonds between nucleobases — the building blocks of DNA that are often referred to as the “letters” in the four-letter DNA alphabet.
“What we have discovered is not DNA trying to be like a protein; it’s a DNA that is doing what GFP does but in its own special way,” said Dr. Ferré-D’Amaré.
The researchers said that the findings should speed the development of fluorescent DNA molecules such as lettuce for rapid-diagnostic tests as well as a host of other scientific applications in which a DNA-based fluorescent tag is desirable.
“Studies like this are going to be essential for the creation of new DNA-based tools,” Dr. Jaffrey said.

People with TBI may continue to improve or decline years after their injury, making it a more chronic illness, according to a study published in the June 21, 2023, online issue of Neurology®, the medical journal of the American Academy of Neurology.
“Our results dispute the notion that TBI is a one-time event with a stagnant outcome after a short period of recovery,” said study author Benjamin L. Brett, PhD, of the Medical College of Wisconsin in Milwaukee. “Rather, people with TBI continue to show improvement and decline across a range of areas including their ability to function and their thinking skills.”
The study involved people at 18 level 1 trauma center hospitals with an average age of 41. A total of 917 people had mild TBI and 193 people had moderate to severe TBI. They were matched to 154 people with orthopedic injuries but no head injuries. Participants were followed for up to seven years.
Participants took three tests on thinking, memory, mental health and ability to function with daily activities annually from two to seven years post-injury. They also completed an interview on their abilities and symptoms, including headache, fatigue, and sleep disturbances.
When researchers looked at all test scores combined, 21% of people with mild TBI experienced decline, compared to 26% of people with moderate to severe TBI and 15% of people with orthopedic injuries with no head injury.
Among the three tests, researchers saw the most decline over the years in the ability to function with daily activities. On average, over the course of 2 to 7 years post-injury, a total of 29% of those with mild TBI declined in their abilities and 23% of those with moderate to severe TBI.
Yet some people showed improvement in the same area, with 22% of those with mild TBI improving over time and 36% of those with moderate to severe TBI.
“These findings point out the need to recognize TBI as a chronic condition in order to establish adequate care that supports the evolving needs of people with this condition,” Brett said. “This type of care should place a greater emphasis on helping people who have shown improvement continue to improve and implementing greater levels of support for those who have shown decline.”
A limitation of the study was that all participants were seen at a level 1 trauma center hospital within 24 hours of their injury, so the findings may not apply to other populations.
The study was funded by the National Institute of Neurological Disorders and Stroke, National Institute on Aging, the National Football League Scientific Advisory Board and the U.S. Department of Defense.

A University of California, Irvine-led team of researchers have discovered that extracts from plants used by the Kwakwaka’wakw First Nations peoples in their traditional botanical medicine practices are able to rescue the function of ion channel proteins carrying mutations that cause human Episodic Ataxia.
The study, “Native American ataxia medicines rescue ataxia-linked mutant potassium channel activity via binding to the voltage sensing domain” was published in June in Nature Communications.
“Episodic Ataxia 1 (EA1) is a movement disorder caused by inherited mutations in the human KCNA1 gene, which encodes Kv1.1, a voltage-gated potassium channel essential for normal function of the human nervous system,” said Geoffrey W. Abbott, PhD, vice dean of basic science research and professor in the Department of Physiology & Biophysics at the UCI School of Medicine. “We found that extracts of stinging nettle, bladderwrack kelp and Pacific ninebark can all correct function of the mutation- carrying proteins causing a specific form of ataxia.”
Abbott’s research team also found that two compounds contained in these plants, tannic acid and gallic acid, are each able to rescue activity of the EA1-linked mutation-carrying ion channel proteins.
“The plant compounds are the first known compounds to rescue the activity of Kv1.1 carrying EA1-linked loss-of-function sequence variants,” said Abbott. “Gallic acid in particular is of therapeutic interest because it is already available over the counter as a nutritional supplement and is very well tolerated in toxicity studies.”
Individuals with ataxia exhibit abnormal gait, slurring, eye movement abnormalities, difficulties with balance and walking, tremors, and disruption of fine motor skills.
“These mutations can cause other disorders, including epilepsy, and so there is therapeutic potential for those conditions as well, ” said Abbott. “We have discovered that where modern synthetic drug development techniques have failed to produce a drug that directly rescues EA1-linked mutant channel function, traditional botanical medicine developed by North American First Nation peoples has succeeded.”
Further research is now needed to explore the efficacy of the plant-derived compounds in preclinical and clinical studies.
“We have made a mouse model of a relatively severe form of human EA1 so that we can test the efficacy and safety of gallic acid and also whole plant extracts,” said Abbott. “If the preclinical studies go well, our goal is to move to clinical trials. Concurrently, we are synthesizing and testing other plant compounds and derivatives to discover other compounds with potential for treating EA1 and related disorders.”
There are several forms of ataxia, which is an umbrella term describing loss of coordination or balance.
Together with Abbott, the research team comprised Drs. Rian Manville, J. Alfredo Freites, Doug Tobias (UC Irvine) and Richard Sidlow (Valley Children’s Hospital). This work was supported by the National Institutes of Health and the National Institute of General Medical Sciences.

If you’ve ever thought you may be running a temperature yet couldn’t find a thermometer, you aren’t alone. A fever is the most commonly cited symptom of COVID-19 and an early sign of many other viral infections. For quick diagnoses and to prevent viral spread, a temperature check can be crucial. Yet accurate at-home thermometers aren’t commonplace, despite the rise of telehealth consultations.
There are a few potential reasons for that. The devices can range from $15 to $300, and many people need them only a few times a year. In times of sudden demand — such as the early days of the COVID-19 pandemic — thermometers can sell out. Many people, particularly those in under-resourced areas, can end up without a vital medical device when they need it most.
To address this issue, a team led by researchers at the University of Washington has created an app called FeverPhone, which transforms smartphones into thermometers without adding new hardware. Instead, it uses the phone’s touchscreen and repurposes the existing battery temperature sensors to gather data that a machine learning model uses to estimate people’s core body temperatures. When the researchers tested FeverPhone on 37 patients in an emergency department, the app estimated core body temperatures with accuracy comparable to some consumer thermometers. The team published its findings March 28 in Proceedings of the ACM on Interactive, Mobile, Wearable and Ubiquitous Technologies.
“In undergrad, I was doing research in a lab where we wanted to show that you could use the temperature sensor in a smartphone to measure air temperature,” said lead author Joseph Breda, a UW doctoral student in the Paul G. Allen School of Computer Science & Engineering. “When I came to the UW, my adviser and I wondered how we could apply a similar technique for health. We decided to measure fever in an accessible way. The primary concern with temperature isn’t that it’s a difficult signal to measure; it’s just that people don’t have thermometers.”
The app is the first to use existing phone sensors and screens to estimate whether people have fevers. It needs more training data to be widely used, Breda said, but for doctors, the potential of such technology is exciting.
“People come to the ER all the time saying, ‘I think I was running a fever.’ And that’s very different than saying ‘I was running a fever,'” said Dr. Mastafa Springston, a co-author on the study and a UW clinical instructor at the Department of Emergency Medicine in the UW School of Medicine. “In a wave of influenza, for instance, people running to the ER can take five days, or even a week sometimes. So if people were to share fever results with public health agencies through the app, similar to how we signed up for COVID exposure warnings, this earlier sign could help us intervene much sooner.”
Clinical-grade thermometers use tiny sensors known as thermistors to estimate body temperature. Off-the-shelf smartphones also happen to contain thermistors; they’re mostly used to monitor the temperature of the battery. But the UW researchers realized they could use these sensors to track heat transfer between a person and a phone. The phone touchscreen could sense skin-to-phone contact, and the thermistors could gauge the air temperature and the rise in heat when the phone touched a body.

To test this idea, the team started by gathering data in a lab. To simulate a warm forehead, the researchers heated a plastic bag of water with a sous-vide machine and pressed phone screens against the bag. To account for variations in circumstances, such as different people using different phones, the researchers tested three phone models. They also added accessories such as a screen protector and a case and changed the pressure on the phone.
The researchers used the data from different test cases to train a machine learning model that used the complex interactions to estimate body temperature. Since the sensors are supposed to gauge the phone’s battery heat, the app tracks how quickly the phone heats up and then uses the touchscreen data to account for how much of that comes from a person touching it. As they added more test cases, the researchers were able to calibrate the model to account for the variations in things such as phone accessories.
Then the team was ready to test the app on people. The researchers took FeverPhone to the UW School of Medicine’s Emergency Department for a clinical trial where they compared its temperature estimates against an oral thermometer reading. They recruited 37 participants, 16 of whom had at least a mild fever.
To use FeverPhone, the participants held the phones like point-and-shoot cameras — with forefingers and thumbs touching the corner edges to reduce heat from the hands being sensed (some had the researcher hold the phone for them). Then participants pressed the touchscreen against their foreheads for about 90 seconds, which the researchers found to be the ideal time to sense body heat transferring to the phone.
Overall, FeverPhone estimated patient core body temperatures with an average error of about 0.41 degrees Fahrenheit (0.23 degrees Celsius), which is in the clinically acceptable range of 0.5 C.
The researchers have highlighted a few areas for further investigation. The study didn’t include participants with severe fevers above 101.5 F (38.6 C), because these temperatures are easy to diagnose and because sweaty skin tends to confound other skin-contact thermometers, according to the team. Also, FeverPhone was tested on only three phone models. Training it to run on other smartphones, as well as devices such as smartwatches, would increase its potential for public health applications, the teamsaid.
“We started with smartphones since they’re ubiquitous and easy to get data from,” Breda said. “I am already working on seeing if we can get a similar signal with a smartwatch. What’s nice, because watches are much smaller, is their temperature will change more quickly. So you could imagine having a user put a Fitbit to their forehead and measure in 10 seconds whether they have a fever or not.”
Shwetak Patel, a UW professor in the Allen School and the electrical and computer engineering department, was a senior author on the paper, and Alex Mariakakis, an assistant professor in the University of Toronto’s computer science department, was a co-author. This research was supported by the University of Washington Gift Fund.

People with amyotrophic lateral sclerosis (ALS) who eat more foods high in certain omega-3 fatty acids like flaxseed oil, walnuts, canola oil and pumpkin seeds may have a slower physical decline from the disease and may have a slightly extended survival. The study, which looked at the survival of people with ALS over the course of 18 months, was published in the June 21, 2023, online issue of Neurology®, the medical journal of the American Academy of Neurology. Researchers also found an omega-6 fatty acid may be beneficial. The study does not prove that these omega fatty acids slow decline of ALS or extend survival; it only shows an association.
ALS is a rare, progressive neurodegenerative disease that affects nerve cells in the brain and the spinal cord. People with ALS lose the ability to initiate and control muscle movement, which often leads to total paralysis and death. The average life span after diagnosis is two to five years.
“The link our study found between diet and ALS is intriguing and suggests, but does not prove, that people with ALS may benefit from incorporating more omega-3 fatty acids into their diet,” said Kjetil Bjornevik, MD, PhD, of Harvard University in Boston, Massachusetts, and member of the American Academy of Neurology. “It will now be important to conduct additional research looking specifically at the plant-based omega-3 fatty acid alpha-linolenic acid in people with ALS to further explore this possibility.”
The study involved 449 people who had ALS with an average age of 58, who were followed over 18 months. Of the total participants, 126 or 28%, died by the end of the study.
Researchers looked at levels of omega-3 fatty acids in participants’ blood. They divided them into four groups based on lowest to highest amounts.
Participants took a test to assess their disease progression and severity of symptoms. The test measured 12 aspects of physical function including swallowing, speaking, chewing, and the ability to use muscles in the hands, arms, legs and torso, as well as respiratory function. Each category was scored from zero, meaning no ability, to four, meaning normal ability. Total scores ranged between zero to 48, with higher scores indicating better function and less severe symptoms.

Researchers found an omega-3 fatty acid called alpha-linolenic acid was the most beneficial. This acid is found in many seeds and oils, including flaxseed, walnuts, chia, hemp, and many common vegetable oils.
The people with the highest amount of alpha-linolenic acid had an average score of 38.3 at the start of the study, while the people with the lowest amount had an average score of 37.6.
A lower number of people from the group with the most alpha-linolenic acid died during the study, with 21 deaths, or 19%, compared to people in the lowest group, with 37 deaths or 33%.
After adjusting for age, sex and ethnicity, people with the highest amounts of alpha-linolenic acid had a 50% lower risk of death during the study compared to people with the lowest amount.
Higher levels of a specific omega-3 fatty acid called eicosapentaenoic acid that is found in fatty fish and fish oil supplements was also associated with a lower risk of death during the study.
In addition, researchers found an omega-6 fatty acid called linoleic acid that is found in vegetable oils, nuts, meats, seeds and eggs was associated with a lower risk of death during the study.
A limitation of the study is the lack of access to data on the overall diet of the participants, including other nutrients and supplements as well as total caloric intake, which could all be associated with survival time in ALS.
The study was supported by the ALS Association.

Smoke particulates from wildfires could cause between 4,000 and 9,000 premature deaths and cost between $36 to $82 billion per year in the United States, according to new research.
The study, “Quantifying the Premature Mortality and Economic Loss From Wildfire-Induced PM2.5 in the Contiguous U.S.,” published in Science of the Total Environment.
“We think of automobile tailpipes and factory emissions polluting our air,” said Oliver Gao, professor of civil and environmental engineering at Cornell University and a senior author on the study. “We don’t necessarily think about air pollution from natural sources like wildfires.
“Climate change is leading to weather extremes like more storms and hurricanes, but it can also lead to more wildfires,” Gao said. “The Quebec wildfires in early June affected human health hundreds of miles away in the distant cities New York, Philadelphia, Baltimore and Washington.”
Wildfires release fine particulate matter — called PM2.5, which consists of inhalable organic compounds, aerosols and metals that are 2.5 microns or less — substantially smaller than a human hair, which can enter the lungs and bloodstream.
The researchers used satellite wildfire emission and air quality (PM2.5) data gathered from 2012 to 2014 for their current updated model and assessed how smoke from wildfires could impact human health and economies.
Metropolitan regions located near fire sources, such as Los Angeles, Houston and Atlanta, will likely see a large health burden and corresponding economic loss, according to the study.
In the model, the researchers estimated New York City metropolitan area — recently affected the Quebec wildfire in early June — would incur 86 premature deaths resulting from similar events and see $780 million in associated economic costs.
California, Florida, Texas, Georgia, Alabama and North Carolina likely would be the states with the highest number of premature deaths due to the volume of particulate matter distributed by the smoke.
Law and regulations — such as planned events to thin forests — could reduce and mitigate the harmful effects of wildfires, Gao said.
“Wildfire affects our health,” he said. “In this era of climate change, if we remove flammable vegetation and do things like create green fire breaks and reduce the fuel for the fires, we can substantially decrease the harm of smoke downwind in populated areas.”

As men age, some of their cells lose the very thing that makes them biological males — the Y chromosome — and this loss hampers the body’s ability to fight cancer, according to new research from Cedars-Sinai Cancer.
The study, published today in the leading scientific journal Nature, found that loss of the Y chromosome helps cancer cells evade the body’s immune system. This common impact of the aging process in men results in aggressive bladder cancer, but somehow also renders the disease more vulnerable — and responsive — to a standard treatment called immune checkpoint inhibitors.
Based on their research, investigators are developing a test for loss of the Y chromosome in tumors with the goal of helping clinicians tailor immune checkpoint inhibitor treatment for male patients with bladder cancer.
“This study for the first time makes a connection that has never been made before between loss of the Y chromosome and the immune system’s response to cancer,” said Dan Theodorescu, MD, PhD, director of Cedars-Sinai Cancer, the PHASE ONE Distinguished Chair and corresponding author of the publication, who initiated the research. “We discovered that loss of the Y chromosome allows bladder cancer cells to elude the immune system and grow very aggressively.”
Lead collaborators on the study also included Johanna Schafer, a postdoctoral fellow, and Zihai Li, MD, PhD, medical oncologist and immunologist, both at The Ohio State University Comprehensive Cancer Center-James Cancer Hospital and Solove Research Institute.
In humans, each cell normally has one pair of sex chromosomes; men have one X and one Y chromosome, while women have two X chromosomes. In men, loss of the Y chromosome has been observed in several cancer types, including 10%-40% of bladder cancers. Loss of the Y chromosome also has been associated with heart disease and Alzheimer’s disease.

The Y chromosome contains the blueprints for certain genes. Based on the way these genes are expressed in normal cells in the bladder lining, investigators developed a scoring system to measure loss of the Y chromosome in cancers.
The investigators then reviewed data on two groups of men. One group had muscle invasive bladder cancer and had their bladders removed, but were not treated with an immune checkpoint inhibitor. The other group participated in a clinical trial and were treated with an immune checkpoint inhibitor. They found that patients with loss of the Y chromosome had poorer prognosis in the first group and much better overall survival rates in the latter.
To determine why this happens, investigators next compared growth rates of bladder cancer cells from laboratory mice.
The investigators grew cancer cells in a dish where the cells were not exposed to immune cells. The researchers also grew the diseased cells in mice that were missing a type of immune cell called T-cells. In both cases, tumors with and without the Y chromosome grew at the same rate.
In mice with intact immune systems, tumors lacking the Y chromosome grew at a much faster rate than did tumors with the intact Y chromosome.

“The fact that we only see a difference in growth rate when the immune system is in play is the key to the ‘loss-of-Y’ effect in bladder cancer,” Theodorescu said. “These results imply that when cells lose the Y chromosome, they exhaust T-cells. And without T-cells to fight the cancer, the tumor grows aggressively.”
Based on their results derived from human patients and laboratory mice, Theodorescu and his team also concluded that tumors missing the Y chromosome, while more aggressive, were also more vulnerable and responsive to immune checkpoint inhibitors. This therapy, one of the two mainstay bladder cancer treatments available to patients today, reverses T-cell exhaustion and allows the body’s immune system to fight the cancer.
“Fortunately, this aggressive cancer has an Achilles’ heel, in that it is more sensitive than cancers with an intact Y chromosome to immune checkpoint inhibitors,” said Hany Abdel-Hafiz, PhD, associate professor at Cedars-Sinai Cancer and co-first author of the study with Schafer and Xingyu Chen, a research bioinformatician at Cedars-Sinai.
Preliminary data not yet published shows that loss of the Y chromosome also renders prostate cancers more aggressive, Theodorescu said.
“Our investigators postulate that loss of the Y chromosome is an adaptive strategy that tumor cells have developed to evade the immune system and survive in multiple organs,” said Shlomo Melmed, MB, ChB, executive vice president of Academic Affairs and dean of the Medical Faculty at Cedars-Sinai. “This exciting advance adds to our basic understanding of cancer biology and could have far-reaching implications for cancer treatment going forward.”
Further work is needed to help investigators understand the genetic connection between loss of the Y chromosome and T-cell exhaustion.
“If we could understand those mechanics, we could prevent T-cell exhaustion,” Theodorescu said. “T-cell exhaustion can be partially reversed with checkpoint inhibitors, but if we could stop it from happening in the first place, there is much potential to improve outcomes for patients.”
While women do not have a Y chromosome, Theodorescu said these findings could have implications for them as well. The Y chromosome contains a set of related genes, called paralogue genes, on the X chromosome, and these might play a role in both women and in men. Additional research is needed to determine what that role might be.
“Awareness of the significance of Y chromosome loss will stimulate discussions about the importance of considering sex as a variable in all scientific research in human biology,” Theodorescu said. “The fundamental new knowledge we provide here may explain why certain cancers are worse in either men or women, and how best to treat them. It also illustrates that the Y chromosome does more than determine human biologic sex.”

A gel that combines both stiffness and toughness is a step forward in the bid to create biodegradable implants for joint injuries, according to new UBC research.
Mimicking articular cartilage, found in our knee and hip joints, is challenging. This cartilage is key to smooth joint movement, and damage to it can cause pain, reduce function, and lead to arthritis. One potential solution is to implant artificial scaffolds made of proteins that help the cartilage regenerate itself as the scaffold biodegrades. How well the cartilage regenerates is linked to how well a scaffold can mimic the biological properties of cartilage, and to date, researchers have struggled to combine the seemingly incompatible properties of stiffness and toughness.
Now, new research by Canadian and Chinese scientists published today in Natureoutlines a method to marry these properties in a biodegradable gel. “Cartilage is tricky,” says senior author Dr. Hongbin Li, a professor in the UBC department of chemistry. “Articular cartilage repair represents an important medical challenge because naturally speaking, it doesn’t repair itself.
Biodegradable cartilage implants must strike a delicate balance in that they need to be both stiff and tough, like actual cartilage. Mechanically, when something is stiff, it resists being bent or deformed, but that usually means it’s brittle — when you bend it, it breaks, like glass. When something is tough, it resists breaking, even when you bend it, but it might be too soft to be useful in a joint, like jelly, or even just softer than actual cartilage. That’s the case with current implants that are made from proteins, which creates a mismatch between what the cells need and what’s being provided, says Dr. Li. This leads to the cartilage not repairing as well as it could.
In the study, Dr. Li and his team developed a new approach to stiffen a protein gel without sacrificing toughness, by physically tangling together the chains of a particular protein that made up the gel’s network. “These entangled chains can move, which allows energy, for instance, the impact from jumping, to be dissipated, just like shock absorbers in bikes. In addition, we combined this with an existing method of folding and unfolding proteins, which also allows for energy dissipation,” says first author Dr. Linglan Fu, who conducted the research as a doctoral student at UBC’s department of chemistry.
The resulting gel was super tough, able to resist slicing with a scalpel, and was more stiff than other protein hydrogels. Its ability to resist compression was among the highest achieved by any such gels and compared favorably with actual articular cartilage. And the gel was able to rapidly recover its original shape after compression, as real cartilage does after jumping.
Rabbits implanted with the gel showed notable signs of repair of articular cartilage 12 weeks after implantation, with no hydrogel remaining and no rejection of the implant by the animals’ immune system. The researchers observed bone tissue growth similar to the existing tissue, and regenerated tissue close to existing cartilage for the gel implant group — much better results than they saw with a control group.
Interestingly, a stiffer version of the gel had better results than a softer version, likely due to the higher stiffness being more compatible with bone and cartilage tissues, and so providing a physical cue to the body for effective regeneration. However, there can be such a thing as too stiff: the stiffest gel did not work as well, likely due to its slower degradation in the body, the researchers said. “This just shows how complex this area of research is, and the need to take into account the many different physical and biochemical cues and factors when designing these scaffolds,” says co-author Dr. Qing Jiang, a professor and surgeon at Nanjing University.
Further animal testing is needed and the research is still premature for human trials. The researchers’ next steps include this testing, fine-tuning the current gel composition and adding additional biochemical cues to further promote cell regeneration. “By optimizing both biochemical and biomechanical cues together, we will see in the future whether these new scaffolds can lead to even better outcomes,” Dr. Li says.

In a new paper published today in Nature, researchers at the Francis Crick Institute have outlined the structure and function of a protein complex which is required to repair damaged DNA and protect against cancer.
Every time a cell replicates, mistakes can happen in the form of mutations, but specialised proteins exist to repair the damaged DNA.
People with mutations in a DNA repair protein called BRCA2 are predisposed to breast, ovarian and prostate cancers, which often develop at a young age. In the clinic, these cancers are treated with a drug that inhibits PARP, another protein needed for DNA repair.
Recent work shows that defects in several other proteins can cause inheritable breast and ovarian cancers or Fanconi anaemia, a blood disorder that can lead to different cancers, including leukaemia.
The researchers used cryo-electron microscopy to reveal the atomic structure of four of these proteins, which come together to form a complex called BCDX2. This allowed them to map mutations associated with cancer on the 3D structure, revealing the important regions of the complex, and why certain mutations prevent DNA repair, leading to an instability in a person’s genes and cancer.
In addition, the researchers discovered BCDX2’s role in the cell, finding that it acts as a ‘molecular chaperone’ — it helps target another protein called RAD51, causing it to recognise and assemble at regions where DNA repair needs to take place. Together, BRCA2, BCDX2 and RAD51 are the main players in the process that repairs damaged DNA — called ‘homologous recombination’.

The research shows that BCDX2 is just as important for repairing DNA as BRCA2, suggesting mutations should also be routinely screened for.
Luke Greenhough, co-first author and postdoctoral research assistant at the Crick, said: “For the first time, we’ve been able to show the direct links between structure, function and why mutations in any of the components of BCDX2 leads to cancer. We now understand its crucial role in DNA repair, which explains why mutations can lead to cancer.”
Eric Liang, co-first author and postdoctoral fellow at the Crick, said: “Just five years ago we wouldn’t have been able to do this — the rapid advance of technology has made this research possible. DeepMind’s AlphaFold2 (a computer programme which can predict a protein’s 3D structure), cryo-EM and high-resolution imaging techniques allowed us to gather the full picture of structure and function for this key protein complex. It was a very collaborative project, spanning multiple labs and technical teams across the Crick.”
The research today could help inform the best line of treatment for people living with cancer.
Steve West, group leader of the DNA Recombination and Repair Laboratory at the Crick, said: “BRCA2 is well characterised and known to increase the risk of cancer, especially breast and ovarian cancers. It’s mutated in 15-20% of inheritable cancer cases so is regularly screened for.
“Our research has shown that BCDX2 is also crucial for DNA repair and acts in the same pathway as BRCA2. For people with cancers caused by defects in BCDX2, PARP inhibitors are also likely to be effective. Our findings suggest that people with a family history of these cancers should be screened for mutations in the proteins making up BCDX2 to get a full picture of their risk.”
The researchers are now hoping to shed light on another protein complex, CX3, which is also involved in cancer. Putting all these insights together will allow a better understanding of genes which put people at a greater risk of cancer and help with targeted treatment.

Cancer immunotherapy has revolutionized treatment of many forms of cancer by unleashing the immune system response against tumors. Immunotherapies that block checkpoint receptors like PD-1, proteins that limit the capacity of T cells to attack tumors, have become the choice for the treatment of numerous types of solid cancer.
However, the introduction of PD-1-blocking agents can often result in T cells attacking healthy tissues in addition to cancer cells, causing severe, sometimes life-threatening, side effects that can blunt the benefits of immunotherapy.
A new study published by researchers at Yale School of Medicine reveals new insights into how PD-1 functions to maintain healthy tissues, findings that can help scientists predict, treat, or even prevent the side effects of PD-1 blocking immunotherapies.
The study was published June 21 in the journal Nature.
“While we know why blocking checkpoint receptors boosts anti-cancer immune responses, we don’t understand why these immunotherapies also cause adverse events in normal organs,” the authors write. “However, the emergence of these adverse events suggests that checkpoint receptors like PD-1 are involved in the constant protection of healthy tissues from immune attack in normal individuals.”
Currently doctors are not able to predict which individuals are likely to develop such side effects and which healthy organs will be attacked as a consequence of immunotherapy. Side effects may prompt doctors to either suspend immunotherapy or prescribe immunosuppressants, with negative consequences on the anti-cancer effects of immunotherapy.
“Our findings show for the first time that PD-1 has a critical role in preventing T cells from attacking normal tissues in healthy individuals and may one day help find ways to reduce or prevent the side effects of immunotherapy,” said Yale’s Nikhil Joshi, associate professor of immunobiology and senior author of the study.
For the study, a team led by Martina Damo, an associate research scientist in the Joshi lab, developed new generation mouse models to address the role of PD-1 in preventing T cells from attacking healthy skin. They mimicked immunotherapy by blocking PD-1 and found mice developed some of the same skin disorders observed in cancer patients treated with PD-1 blockers.
The data in mice were corroborated by analysis of skin biopsies obtained from cancer patients under treatment at the Yale Onco-Dermatology Program at Smilow Cancer Hospital at Yale New Haven, which is directed by Dr. Jonathan Leventhal.
“Our data in mice and humans support the hypothesis that checkpoint receptors like PD-1 function as gatekeepers of tissue homeostasis by allowing the presence of functional T cells in peripheral tissues without immunopathology,” Damo said. “We propose that PD-1-blocking immunotherapies interfere with these physiological regulatory functions, thus resulting in adverse events. This study lays the ground for the future development of improved immunotherapies that avoid adverse events.”