Publisher Health

A multi-institutional study co-authored by University of Texas at Arlington scientists uncovered a mechanism by which cancer cells prevent the immune system from activating and attacking the cancerous invaders.
The study, published in the peer-reviewed journal Cell Reports, sheds light on why immunotherapy treatments don’t work for all people or all diseases. For example, certain types of cancers — including colon, pancreatic, prostate and brain cancers — have stubbornly resisted immunotherapy. And while breast, esophageal and head and neck cancers often respond favorably, sometimes the treatments don’t work as planned. Researchers still don’t understand exactly why.
“Immunotherapy is an incredibly promising new treatment avenue for cancer, but we still have work to do determining why it doesn’t work for all people or types of cancer,” said Jon Weidanz, UTA associate vice president for research and innovation.
He and Soroush Ghaffari, a UTA postdoctoral fellow, were co-authors of the study, along with colleagues at Leiden University in Leiden, Netherlands, and Karolinska University in Solna, Sweden. The team determined that a key checkpoint in the immune system — called NKG2A — doesn’t engage with its specific binding molecule expressed in cancer cells until the appropriate signal is received.
“The team reasoned that monotherapy agents targeting the NKG2A receptor may not be effective without receiving an inflammatory trigger,” Ghaffari said. “This might explain why drugs designed to bind to the NKG2A receptor to disrupt this immune checkpoint have been only effective when used in combination with other agents that can induce the necessary inflammatory signal.”
A second major finding of the study revealed how certain cancers can inhibit the immune system from activating its macrophages, which are specialized immune cells that play a critical role in eliminating diseased or damaged cells.
“These data give us a new molecular understanding of why some immunotherapies work and some don’t,” said Weidanz, who also is a professor kinesiology with an appointment in bioengineering and a member of the Multi-Interprofessional Center for Health Informatics. “These results will help us identify and treat more cancers effectively with immunotherapy, helping more people live longer lives despite a cancer diagnosis.”
These findings have implications for immune system research and the development of more effective immunotherapy drugs, said Kate C. Miller, vice president of research and innovation at UTA.
“These are exciting new research results that have the potential to impact people living with cancer,” Miller said. “This is another great example of the caliber of biomedical research we’re performing both here at UTA and with our partners at other institutions.”

New King’s College London research reveals that interventions which improve mood can reduce levels of inflammation in people with inflammatory bowel disease by 18 per cent, compared to having no mood intervention.
Researchers at the Institute of Psychiatry, Psychology & Neuroscience at King’s College London found that interventions designed to improve mood, including psychological therapy, antidepressants, and exercise, were associated with significant reductions in inflammatory biomarker levels in individuals with inflammatory bowel disease (IBD). Interventions for mood may present an alternative treatment for IBD that is both effective and low-cost.
The research — supported by the National Institute for Health and Care (NIHR) and Medical Research Council (MRC) — indicates that interventions for mood can present an alternative treatment for IBD that is both effective and low-cost.
IBD, comprising Crohn’s disease and ulcerative colitis, is a chronic autoimmune condition affecting over 500,000 people in the UK that causes inflammation of the digestive tract. This results in abdominal pain, diarrhea, fatigue, incontinence, and other debilitating symptoms. Alongside the physical symptoms, IBD can have major implications on mental health and wellbeing.
Inflammatory biomarkers can be found in the body to indicate areas and types of inflammation. Researchers analysed existing studies on levels of the biomarkers C-Reactive Protein and faecal calprotectin which are specific indicators of IBD, as well as a combined measure of other inflammatory biomarkers.
The systematic review and meta-analysis published in eBiomedicine, part of The Lancet Discovery Science, is the first to investigate the relationship between interventions aiming to treat mood and levels of inflammatory biomarkers in IBD. The findings suggest that interventions for mood present a strategy to improve mental health and reduce inflammation in IBD.
Natasha Seaton, first author of the study and PhD student at King’s IoPPN, said:
“IBD is a distressing condition and current medication that reduces inflammation is expensive and can have side effects. Our study showed that interventions that treat mental health reduce levels of inflammation in the body. This indicates that mood interventions could be a valuable tool in our approach to help those with IBD.”

The researchers conducted a search of more than 15,000 articles, looking for all randomised controlled trials in adults with IBD that measured levels of inflammatory biomarkers and tested a mood intervention (for example, interventions to reduce depression, anxiety, stress and distress, or improve emotional wellbeing).
They reviewed and analysed data from 28 randomised controlled trials involving over 1,700 participants to establish whether interventions targeting mood outcomes impact inflammation levels in IBD.
Researchers found that psychological therapies, including Cognitive Behavioural Therapy (CBT), Acceptance and Commitment Therapy, and Mindfulness Based Stress Reduction, had the best outcomes on inflammation in IBD, compared with antidepressants and exercise interventions. Interventions which had a larger positive effect on mood had a greater effect on reducing inflammatory biomarkers. These findings suggest that the mechanism underlying the effect of psychological and social interventions on inflammation in IBD could be improved mood.
Individual analyses on IBD-specific inflammatory markers revealed a small reduction in C-Reactive Protein and faecal calprotectin following mood intervention. This suggests that treatments which improve mood have beneficial effects on generic inflammation as well as disease-specific biomarkers.
Professor Valeria Mondelli, co-lead of the Psychosis and Mood Disorders Theme at the NIHR Maudsley BRC and Clinical Professor of Psychoneuroimmunology at King’s IoPPN, said:
“Our study suggests that improvements in mood can influence physical diseases through modulation of the immune system. We know stress-related feelings can increase inflammation and the findings suggest that by improving mood we can reduce this type of inflammation. This adds to the growing body of research demonstrating the role of inflammation in mental health and suggests that interventions working to improve mood could also have direct physical effects on levels of inflammation. However, more research is needed to understand exact mechanisms in IBD.”
Many IBD medications have negative side effects, and they are often very costly. For example, the anti-inflammatory medication infliximab costs about £12,584 per year. The study suggests that interventions that aim to improve mood, particularly psychological therapies costing approximately £480-£800 in the UK (an eight-week course of face-to-face CBT) could reduce inflammation in IBD and potentially provide an alternative treatment or one that works alongside medication to reduce costs and increase effectiveness.

Professor Rona Moss-Morris, Digital Therapies theme lead at NIHR Maudsley BRC, Professor Psychology as Applied to Medicine at King’s IoPPN, and senior author of the study, said:
“Interventions for mood show considerable promise for the management of IBD in improving mental health, inflammation, and disease outcomes. Integrated mental health support alongside pharmacological treatments may offer a more holistic approach to IBD care, potentially leading to reduced disease and healthcare costs. Currently, medications taken to reduce inflammation are often very costly compared to psychological therapies in the UK. Given this, including psychological interventions, such as cost-effective digital interventions, within IBD management might reduce the need for anti-inflammatory medication, resulting in an overall cost benefit.”
This study was funded by the NIHR Maudsley Biomedical Research Centre (BRC), hosted by South London and Maudsley NHS Foundation Trust in partnership with King’s College London, and the Medical Research Council. Natasha Seaton is funded by an MRC Doctoral Training Partnership.

A new study co-led by investigators from Mass Eye and Ear, a member of Mass General Brigham, demonstrated the effectiveness of a gene therapy towards restoring hearing function for children suffering from hereditary deafness. In a trial of six children taking place at the Eye & ENT Hospital of Fudan University in Shanghai, China, the researchers found the novel gene therapy to be an effective treatment for patients with a specific form of autosomal recessive deafness caused by mutations of the OTOF (otoferlin) gene, called DFNB9. With its first patient treated in December 2022, this research represents the first human clinical trial to administer gene therapy for treating this condition, with the most patients treated and longest follow-up to date. Their results are published January 24th in The Lancet.
“If children are unable to hear, their brains can develop abnormally without intervention,” said Zheng-Yi Chen, DPhil, an associate scientist in the Eaton-Peabody Laboratories at Mass Eye and Ear and associate professor of Otolaryngology-Head and Neck Surgery at Harvard Medical School. “The results from this study are truly remarkable. We saw the hearing ability of children improve dramatically week by week, as well as the regaining of their speech.”
Hearing loss affects more than 1.5 billion people worldwide, with congenital deafness making up about 26 million of those individuals. For hearing loss in children, more than 60 percent stem from genetic reasons. DFNB9 for example, is a hereditary disease caused by mutations of the OTOF gene and a failure to produce a functioning otoferlin protein, which is necessary for the transmission of the sound signals from the ear to the brain. There are currently no FDA-approved drugs to help with hereditary deafness, which has opened the door for new solutions like gene therapies.
In order to test this novel treatment, six children with DFNB9 were observed over a 26-week period at the Eye & ENT Hospital of Fudan University. The Mass Eye and Ear collaborators utilized an adeno-associated virus (AAV) carrying a version of the human OTOF gene to carefully introduce the gene into the inner ears of the patients through a special surgical procedure. Differing doses of the single injection of the viral vector were used.
All six children in the study had total deafness, as indicated by an average auditory brainstem response (ABR) threshold of over 95 decibels. After 26 weeks, five children demonstrated hearing recovery, showing a 40-57 decibel reduction in ABR testing, dramatic improvements in speech perception and the restored ability to conduct normal conversation. Overall, no dose-limiting toxicity was observed. While following up on the patients, 48 adverse events were observed, with a significant majority (96%) being low grade, and the rest being transitory with no long-term impact.
Trial findings will also be presented February 3rd at the Association for Research in Otolaryngology Annual Meeting.
This study provides evidence towards the safety and effectiveness of gene therapies in treating DFNB9, as well as their potential for other forms of genetic hearing loss. Moreover, the results contribute to an understanding of the safety of AAV insertion into the human inner ear. In regard to the usage of AAVs, the success of a dual-AAV vector carrying two pieces of the OTOF gene is notable. Typically, AAVs have a gene size limit, and so for a gene like OTOF that exceeds that limit, the achievement with a dual viral vector opens the door for AAV’s use with other large genes that are typically too big for the vector.
“We are the first to initiate the clinical trial of OTOF gene therapy. It is thrilling that our team translated the work from basic research in animal model of DFNB9 to hearing restoration in children with DFNB9,” said lead study author Yilai Shu, MD, of the Eye & ENT Hospital of Fudan University at Fudan University. Shu previously served as a postdoctoral fellow in Chen’s lab at Mass Eye and Ear. “I am truly excited about our future work on other forms of genetic hearing loss to bring treatments to more patients.”
The researchers plan to expand the trial to a larger sample size as well as track their outcomes over a longer timeline.
“Not since cochlear implants were invented 60 years ago, has there been an effective treatment for deafness,” said Chen. “This is a huge milestone that symbolizes a new era in the fight against all types of hearing loss.”

Menopausal women who regularly swim in cold water report significant improvements to their physical and mental symptoms, finds a new study led by UCL researchers.
The research, published in Post Reproductive Health, surveyed 1114 women, 785 of which were going through the menopause, to examine the effects of cold water swimming on their health and wellbeing.
The findings showed that menopausal women experienced a significant improvement in anxiety (as reported by 46.9% of the women), mood swings (34.5%), low mood (31.1%) and hot flushes (30.3%) as a result of cold water swimming.
In addition, a majority of women (63.3%) swam specifically to relieve their symptoms.
Some of the women quoted in the study said that they found the cold water to be “an immediate stress/ anxiety reliever” and described the activity as “healing.”
One 57-year-old woman stated: “Cold water is phenomenal. It has saved my life. In the water, I can do anything. All symptoms (physical and mental) disappear and I feel like me at my best.”
Senior author, Professor Joyce Harper (UCL EGA Institute for Women’s Health), said: “Cold water has previously been found to improve mood and reduce stress in outdoor swimmers, and ice baths have long been used to aid athletes’ muscle repair and recovery.

“Our study supports these claims, meanwhile the anecdotal evidence also highlights how the activity can be used by women to alleviate physical symptoms, such as hot flushes, aches and pains.
“More research still needs to be done into the frequency, duration, temperature and exposure needed to elicit a reduction in symptoms. However, we hope our findings may provide an alternative solution for women struggling with the menopause and encourage more women to take part in sports.”
Most of the women involved in the study were likely to swim in both summer and winter and wear swimming costumes, rather than wet suits.
Alongside aiding menopausal symptoms, the women said their main motivations for cold water swimming were being outside, improving mental health and exercising.
Professor Harper said: “The majority of women swim to relieve symptoms such as anxiety, mood swings and hot flushes. They felt that their symptoms were helped by the physical and mental effects of the cold water, which was more pronounced when it was colder.
“How often they swam, how long for and what they wore were also important. Those that swam for longer had more pronounced effects. The great thing about cold water swimming is it gets people exercising in nature, and often with friends, which can build a great community.”
The researchers also wanted to investigate whether cold water swimming improved women’s menstrual symptoms.

Of the 711 women who experienced menstrual symptoms, nearly half said that cold water swimming improved their anxiety (46.7%), and over a third said that it helped their mood swings (37.7%) and irritability (37.6%).
Yet despite the benefits of cold water swimming, the researchers were also keen to highlight that the sport comes with certain risks.
Professor Harper explained: “Caution must be taken when cold water swimming, as participants could put themselves at risk of hypothermia, cold water shock, cardiac rhythm disturbances or even drowning.
“Depending on where they are swimming, water quality standards may also vary. Raw sewage pollution is an increasingly common concern in UK rivers and seas. And, sadly, this can increase the likelihood of gastroenteritis and other infections.”
Study limitations
The study may contain some bias due to the survey only being taken by women who already cold water swim. And, as the survey was conducted online, it is likely that women were more likely to complete the survey if they noticed an association between menopause symptoms and cold water swimming.

In findings that have implications for potential new HIV therapies, researchers from Texas Biomedical Research Institute (Texas Biomed) used genetic sequencing techniques on the nonhuman primate version of the virus to identify that lymph nodes in the abdomen are the leading source of rebound infection after the first week of stopping antiretroviral treatment.
The study regarding simian immunodeficiency virus (SIV) was reported in the journal Science Translational Medicine. SIV is very closely related to HIV and is commonly used as a proxy to study HIV in animal models.
“Lymphoid tissues are known to be large reservoirs of latent HIV,” says Texas Biomed Professor Binhua “Julie” Ling, MD, PhD, and senior paper author. “However, there has been no definitive proof that they are the source of initial viral rebound — it has been a hypothesis. Now, we have evidence that SIV, and therefore potentially HIV, is hiding in specific types of lymph nodes and spleen tissues and is some of the first to reemerge in blood when treatment is stopped.”
Antiretroviral therapy (ART) does an excellent job at suppressing HIV to undetectable levels in the blood. However, small amounts of latent virus hide throughout the body, including in the brain, lung, gut, spleen, lymph nodes and other organs. When treatment is stopped, it opens the door for the virus to rebound.
“If we can identify the starting point of the virus rebound, we can work on developing treatments that target those tissues and stop the virus from spreading in the first place,” Dr. Ling says.
Dr. Ling and her team used several advanced genetic tools and sequencing techniques to track the virus. They teamed up with Brandon Keele, PhD, at the AIDS and Cancer Virus Program at Fredrick National Laboratory, who generated barcoded viruses. More than 9,000 individual viruses in the stock have unique genetic barcodes, “like when you go to Walmart and each item has its unique barcode to scan,” Dr. Ling explains.
Those barcoded viruses were given to seven nonhuman primates. After infection was established, the primates began receiving antiretroviral therapy. After four to six months on ART, the animals had either very small amounts or no detectable virus circulating in blood, much like people living with HIV who are on ART. When treatment was stopped after more than a year of ART, researchers were able to assess the very earliest stages of viral rebound.

Thanks to the barcoded viruses, they could identify in which tissues the virus had replicated the fastest and spread the furthest just seven days after treatment was stopped. They matched the barcodes most prevalent in blood plasma to the barcodes detected in specific tissues. Notably, the standard test did not detect any virus in blood at the seven-day mark — the amounts present were too low to be detected — but more sensitive deep sequencing did.
The researchers found three leading contributors: mesenteric lymph nodes, which are found in the tissue connecting the intestines to the abdominal wall; the spleen, which is a part of the lymphatic system that filters blood; and inguinal lymph nodes, which are located in the groin.
Through additional analyses, the researchers found CD4 T cells, a type of immune cell, in the mesenteric lymph nodes and spleen had higher amounts of intact virus and replication activity, which corresponded with higher rates of barcoded viruses from those regions in blood plasma. This was further confirmed using a novel technology by Qingsheng Li, PhD, at University of Nebraska-Lincoln.
Interestingly, some animals showed no evidence of viral rebound, indicating they had better control of the virus in the first week after treatment was stopped than others. Through single cell sequencing and transcriptomic analyses, the team identified a few genes of interest that contribute to dysregulation of normal cell function and could play a role in the differences between animals who experienced very rapid rebound and the animals who continued to suppress viral activity. The researchers are interested in learning more about these genes and how they might affect human immune responses.
The researchers acknowledge that the study size of seven animals is small, and that tissue sample size was also limited. Nonetheless, the results point to key organs to explore specific, targeted therapies.
“There are more than 800 lymph nodes throughout the body,” says Dr. Ling. “Knowing which types of lymph nodes to target can lead to more tailored therapies or treatments and hopefully prevent HIV from spreading and prolong HIV remission.”

UNSW medical researcher Dr David Jacques and his team have discovered how the human immunodeficiency virus (HIV) breaches the cell nucleus to establish infection, a finding that has implications beyond HIV biology.
To infect cells, HIV must enter the target cell and make its way to the nucleus in the cell’s centre where enough copies of its genetic code can be produced to infect other cells.
To safely complete this quest, the virus builds a protective protein coat — a capsid — to shield itself from the host’s immune defences geared to destroy it. Until now, it has remained a mystery exactly how the entire capsid moves through the pores embedded in the nuclear envelope to enter the nucleus.
But the research published in Nature today reveals just how the HIV capsid gets into the nuclear pore barrier channel.
Restricted access
“The nuclear pore complex is made up of a combination of proteins,” said the study’s senior author Dr Jacques of UNSW’s School of Biomedical Sciences.
“While small molecules pass in and out of the nucleus via the nuclear pore complex, traffic is restricted for bulky cargo.

“Larger proteins need to be bound to nuclear transporters — chaperone proteins — that carry them through the multi-layered molecular gate.”
The HIV capsid, despite being a thousand times bigger than the size of molecules that filter through the barrier layers, could pass into the nuclear transport channels without chaperones, Dr Jacques’ team showed.
Chaperone proteins — also called ‘karyopherins’ — engage with the proteins in the middle of the nuclear pore complex in a way that allows them to move with their payload into each successive layer of the molecular gate. Bulky structures without chaperones are excluded from this portal because they are unable to connect with the gate-keeper proteins in the nuclear pore.
HIV using ‘secret handshake’ to get in
The HIV capsid, however, has evolved to interact with the barrier proteins in the same way as the host’s chaperone proteins.
“One of the theories in the field is that HIV hijacks a host chaperone to gain access to the nucleus. But our results show that HIV does not need a chaperone because it is its own chaperone. It’s as though the viral capsid has learned the secret handshake to be permitted into a restricted area by mimicking the chaperones,” Dr Jacques said.

“People made assumptions about how the capsid might get past the selective barrier. Our work is really starting to directly address this, and to me that’s exciting,” said Dr Claire Dickson, co-first author of the study.
The discoveries were enabled by a single-molecule method developed previously by the team that allowed them to systematically screen proteins of the nuclear pore complex to identify those that interacted with the intact HIV capsid.
Dr Jacques is particularly excited about bringing together the collective knowhow of his multidisciplinary team in Australia and the UK, and the crucial infrastructure available at UNSW.
“The only way we were able to deliver this project was by tapping into UNSW’s Mark Wainwright Analytical Centre and the expertise that they brought across the breadth of different technologies and methods that we needed, including protein production, structural biology, super-resolution imaging and electron microscopy,” he said.
“I am really proud of being able to overcome some major challenges with this project, to make a significant impact on the field of HIV research by aiding a better understanding of this process,” said co-first author Dr Sophie Hertel.
Wider implications
The molecular understanding gained in this study about host-pathogen interactions, the authors believe, goes beyond uncovering details of the lifecycle of HIV. This mechanistic knowledge can also be exploited for other applications including gene therapy.
“HIV is one of the most studied pathogens, but we still have so much that we can learn from it. There’s something special about HIV; it can penetrate the nucleus without damaging it or needing to wait for the cell to divide like other viruses. Our observations give us insight that allows us to think about how we deliver cargo into the nucleus,” said Dr Jacques.

Obesity is a problem in the United States. In fact, 42.5% of U.S. adults aged 20 and over have the disease. Not only is obesity the nation’s second leading cause of preventable death (behind only smoking cigarettes), it also leads to other serious health issues, including an increased risk of type 2 diabetes, high blood pressure, heart disease, stroke, cancer, sleep apnea and liver disease. The disease and its side effects impose a significant financial burden on America’s health care system.
As many make — and often fail to keep — New Year’s resolutions about exercise and weight loss goals, University of Missouri researcher Mansoo Yu has completed a long-term study that highlights which specific features of online weight loss interventions are most likely to lead to long-term weight loss and maintenance. Yu found that counseling with professional health coaches and social support from other users are the two most beneficial features of online weight-loss programs for middle-aged adults (ages 35-55) with obesity or overweight.
The findings can help the public choose from among the seemingly infinite number of online weight loss interventions available in today’s digital age.
“Not only are there physical health issues related to obesity, but individuals with obesity are also at higher risk for mental health issues such as depression, poor self-esteem and social isolation,” said Mansoo Yu, a professor in the MU College of Health Sciences. “My research is at the intersection of social work and public health, and my goal is to help people live happier, healthier lives.”
Don’t go at it alone
In the study, Yu collaborated with Kyung Jung Han, a former MU doctoral student who is an associate professor at California State University, Bakersfield. The pair examined 20 years of existing published research on the topic of various online interventions geared toward helping those with obesity lose weight. They identified which online features were associated with the most significant long-term weight loss.
“The three categories of online interventions we evaluated were those that only provided educational information and self-monitoring tools, those that had an online ‘group chat’ function where participants could share their progress with their peers and befriend each other, and finally those that included a professional health coach who could answer any questions participants had,” Yu said. “The interventions with access to social support from other participants or professional health coaches were as effective as in-person weight loss interventions.”
Yu added that for people who live in rural areas, where individuals experience obesity at higher rates, online interventions can provide more accessibility, flexibility and convenience as well as reduce transportation times and costs.

“The key is picking the online intervention with the most effective features, such as access to social support from other participants and professional health coaches,” Yu said. “Our research, which took eight years to complete, combed through 20 years’ worth of published research in order to provide the broader community with the best evidence-based recommendations.”
For those with New Year’s resolutions surrounding weight loss and more exercise, Yu recommends the following tips:
1. Sharing your resolution with friends, family members, significant others and colleagues to increase accountability and social support.
2. Scheduling some form of physical activity into your daily routine.
3. Checking in with others to see how their resolutions are going and offering words of encouragement.
4. Having friendly competition with peers to see who walked or ran more steps each day.
5. Asking professional heath coaches for evidence-based advice when it comes to exercise or diet-related questions.

An immune component of breast milk known as the complement system shapes the gut environment of infant mice in ways that make them less susceptible to certain disease-causing bacteria, according to a study led by researchers at the Johns Hopkins Bloomberg School of Public Health.
The researchers found that mouse pups that nursed from lactating mice whose breast milk lacked a key complement protein had different gut microbe populations than pups that nursed on standard mouse breast milk, making them highly vulnerable to Citrobacter rodentium, a bacterium that infects the guts of mice. Citrobacter rodentium is similar to certain types of diarrhea-causing E. coli that can infect humans but not mice.
The researchers’ experiments suggest that mouse breast milk’s complement components boost mouse infant health by directly eliminating some types of gut-dwelling bacteria. This reshaping of the gut microbiota leaves the infant mice far less susceptible to Citrobacter rodentium infection, thus protecting the young from certain infectious threats. The reshaping activity is not dependent on antibodies, in contrast to the way complement components are thought to typically work.
The researchers also confirmed in separate in vitro analyses that human breast milk contains these complement components, which demonstrated similar activity in targeting specific bacteria.
Taken together, these findings shed light on the mechanisms of how breast milk functions to provide protection from certain bacterial infections.
The study was published online January 18 in the journal Cell.
“These findings reveal a critical role for breast milk complement proteins in shaping offspring’s gut microbe compositions and protecting against bacterial infection in the gut in early life,” says study senior author Fengyi Wan, PhD, a professor in the Bloomberg School’s Department of Biochemistry and Molecular Biology. “This represents an important expansion of our understanding of breast milk’s protective mechanisms.”
The study’s first author is Dongqing Xu, PhD, an assistant scientist in Wan’s research group.

Breastfeeding has many known and suspected benefits. It provides excellent nutrition to infants and appears to protect against some short-term or long-term illnesses. Breast milk is also known to help protect against common infections by sharing antibodies and white blood cells from the mother.
Breast milk also contains complement proteins that can work with, or “complement,” antibodies in attacking bacteria. While complement proteins that circulate in the blood have been the focus of much research, complement proteins in breast milk have been far less studied, and until now their role has been unclear.
In the new study, Wan and his team used engineered mice that lacked critical complement genes. They found that milk from female mice of this type left several-weeks-old mouse pups — even those with normal complement genes — highly susceptible to colitis, often lethal, from Citrobacter rodentium infections. By contrast, pups feeding on normal, complement-containing milk showed only minor and transient signs of gut infection.
The team discovered that this protective effect of breast milk complement proteins depends on their capacity in shaping infant gut microbiota. The complement proteins kill certain gut bacterial species, and this culling of microbes creates an overall gut environment in which harmful inflammation is much less likely in the presence of Citrobacter rodentium.
“Gut microbiota is of great importance to health,” says Wan. “Breast milk complement proteins contribute crucially to the establishment of a ‘protective’ gut microbiota during the early stages of development, promoting infant health and defending against pathogens.”
The study also appears to mark an advance in basic immunology. Complement proteins in blood, although known to be capable of causing direct damage to bacterial cells, have been thought to typically work in partnership with antibodies in a specific immune response. However, Wan and his team showed that this breast milk complement activity against bacteria does not require antibodies and is a nonspecific immune response.
“This opens the door to a lot of new investigations, for example, elucidating the specific complement biology in breast milk and comparing that to complement biology in the blood, and assessing the role of complement beyond the antibody-dependent specific immune system,” Wan says.
Support for the research was provided by the National Institutes of Health (GM111682, AI137719, CA244350); the U.S. Department of Defense (W81XWH-19-1-0479); the American Association of Immunologists; and the American Heart Association (19PRE34380234).

Mass Eye and Ear physician-researchers show that retinal imaging can help predict a person’s risk of developing ocular, neuropsychiatric, cardiac, metabolic, and pulmonary diseases. The team also identified genetic loci associated with retinal thinning, which could help develop personalized treatment plans and future therapies for eye diseases such as glaucoma and macular degeneration.
The retina is said to provide a window into a person’s systemic health. In a new study published January 24th in Science Translational Medicine, physician-researchers from Mass Eye and Ear, a member of Mass General Brigham, and the Broad Institute of MIT and Harvard combined retinal imaging, genetics and big data to estimate how likely a person is to develop eye and systemic diseases in the future. They found significant associations between the thinning of different retinal layers and increased risk of developing ocular, neuropsychiatric, cardiac, metabolic, and pulmonary diseases and identified genes that are associated with retinal layer thickness.
“We showed that retinal images could be used to predict the future risk of both ocular disease and systemic disease,” says first author Seyedeh Maryam Zekavat, MD,PhD, a Harvard Ophthalmology resident at Mass Eye and Ear and graduate student at Broad. “This could potentially help with disease prevention — if we know from someone’s retinal image that they are at high risk of developing glaucoma or cardiovascular disease in the future, we could refer them for follow-up screening or preventative treatment.”
Because of its position behind the transparent structures of the eye, the retina is easy to visualize and image non-invasively, and retinal imaging is already a routine procedure in ophthalmology. The new study uncovers possibilities for preventative medicine and crosstalk between ophthalmologists and other areas of medicine.
Previous studies have shown that there are links between retinal health and health conditions including aging, cardiometabolic diseases such as diabetes and hypertension, and neurological diseases such as dementia, stroke, and multiple sclerosis.
“We’ve come to realize recently that there is a lot more information that we can get from our retina images than we thought was possible,” says senior author Nazlee Zebardast, MD, MSc, director of Glaucoma Imaging at Mass Eye and Ear and an assistant professor of ophthalmology at Harvard Medical School. “It’s really exciting to be able to see that these images, which are obtained without having to do any sort of invasive procedure, are associated with so many systemic conditions, both at a genetic level as well as an epidemiologic level.”
To identify associations between retinal health and disease risk, and to identify genes associated with retinal health, the researchers analyzed data from 44,823 UK Biobank participants who underwent optical coherence tomography (OCT) imaging of the retina, genotyping, and baseline measurements of health in 2010 and were then followed for disease development for an average of ten years.

Unlike previous studies that searched for genes associated with overall retina health, this study delved deeper into the role of the different cell layers that make up the retina.
“Each layer of the retina is made up of different types of cells with diverse structures and functions, and we show that the thicknesses of these different layers are associated with different conditions,” says Zebardast, who is also an associated scientist at Broad.
The study also provides insight into the genes and biological pathways that determine retinal health, which could be leveraged to develop future therapies, the researchers say. Altogether, the team identified 259 genetic loci that were associated with retinal thickness.
One particular insight from this work was that multiple systemic health conditions including poor cardiac, metabolic, pulmonary, and renal function are linked to thinning of the photoreceptor segment of the retina, though further research would be needed to confirm causality. Future studies should also aim to replicate the study’s methods in more diverse populations and different age groups, since participants in the UK BioBank were predominantly white and aged 40-70 years old at baseline.
The study is part of an ongoing effort at Mass Eye and Ear to identify genetic markers of glaucoma and other ocular diseases that might help to develop personalized risk scores and treatment plans for patients. Retinal OCT imaging is already a standard clinical procedure in ophthalmology at Mass Eye and Ear and elsewhere, but the authors say that their results suggest that its use could be widened. Further work on the connection between ocular and cardiometabolic health will enable understanding of its clinical utility, and the researchers are extending this line of research along with co-author Pradeep Natarajan, MD, director of preventive cardiology at Massachusetts General Hospital, and an associate member in the Cardiovascular Disease Initiative at Broad.
“Patients come to us for their eye health, but what if we could tell them more than that?” says Zebardast. “What if we could use someone’s retinal images to tell them, ‘You seem to have a high risk of having high blood pressure, maybe you should get screened, or maybe your primary care doctor should know about that.'”

Biomedical engineers at Duke University have demonstrated that one of the most dangerous mutations found in skin cancers might moonlight as a pathway to mending a broken heart.
The genetic mutation in the protein BRAF, a part of the MAPK signaling pathway that can promote cell division, is one of the most common and most aggressive found in melanoma patients. In a new study, researchers show that introducing this mutation to rat heart tissue grown in a laboratory can induce growth.
Repairing cardiac muscle after a heart attack is the “holy grail” of heart research, complicated by the fact that heart tissue does not regenerate on its own. One potential strategy would be to persuade heart muscle cells to divide by safely delivering a therapeutic gene to patients and fully controlling its activity in the heart.
The new study, appearing online January 24 in the journal Science Advances, lays important steps in finding ways to achieve this goal.
“Mature heart muscle cells do not typically divide, so we thought we’d need an especially strong genetic mutation to convince them to multiply,” said Nenad Bursac, professor of biomedical engineering at Duke. “MAPK is a well understood pathway that, when mutated, can be pretty aggressive at inducing proliferation in cancers, which is why we chose to look into it.”
In the study, Bursac and PhD student Nicholas Strash studied neonatal rat heart cells grown within a 3D hydrogel environment. Developed by the laboratory over more than a decade, the hydrogel environment provides the cues to grow and mature cells into adult-like heart muscle tissues, where cell division naturally stops.
Then, to try to get the muscle to divide and grow again, the researchers infected it with a virus loaded with a mutated BRAF gene. Following its normal behavior, the virus inserted the mutated gene into the cells, causing it to become a part of the cells’ DNA. The researchers then introduced a drug that caused the mutated BRAF genes to activate.

As with skin cancer, once activated, the mutant genes caused the heart muscle cells to enter DNA synthesis — the first step in cell division and growth. But there were also drawbacks.
“Once the cells started entering into their multiplication phase, they also began disassembling the machinery that allows them to contract and pump blood when in the heart,” Strash said. “It caused the tissue as a whole to lose about 70% of its contractile strength, which is pretty dramatic. One reason for this is that almost all cells in the tissue got infected by the virus.”
The results are both exciting and revealing. Any potential therapeutic that can get adult heart cells to proliferate is cause for optimism. But with the accompanying loss of strength, the dosage and duration of gene activation needs to be precisely controlled — thus there’s much to do before any potential use in human patients.
For starters, a different delivery system would have to be applied that can deliver the genes to the correct cells in a way that clinicians can fully control. Methods such as lipid nanoparticles and short-living viruses are two approaches currently being developed, but both still have a ways to go before they could be applied for heart regeneration in humans.
The other major hurdle is finding a way to jump start heart tissue regeneration without causing the tissue to lose strength. Based on the timing of cellular mechanisms, the researchers believe there may be a window in which the mutated gene activity could be stopped after the replication begins, but before the contractile machinery is affected in a large portion of the heart. Or there may be an opportunity to administer a second therapeutic that could prompt the cells to rebuild the dismantled pumping machinery after proliferation.
Moving forward, the researchers are planning to study how this approach works in the hearts of live animals and compare it to their lab-tested results. Working with live animals will also provide a better understanding of what other genes and processes are activated by the mutated BRAF gene, and whether proliferation could be independently activated without functional decline to efficiently promote healing.
“The heart essentially does not have primary cancers, and it’s almost unique that it doesn’t,” Bursac said. “Introducing this cancer mutation in the heart is obviously an engineered outcome that doesn’t happen naturally. Studying it in lab-grown tissues is a great step toward understanding what this entire signaling pathway does within the heart, which could have benefits beyond regenerative therapies.”
The research was supported by the National Institutes of Health (U01HL134764, R01HL164013, 5T32HD040372, 1F31HL156453, 1F31HL162460), the Translating Duke Health Initiative and a Foundation Leducq grant (15CVD03).