Publisher Health

A perplexing problem for people with recurring urinary tract infections (UTIs) is persistent pain, even after antibiotics have successfully cleared the bacteria.
Now Duke Health researchers have identified the likely cause — an overgrowth of nerve cells in the bladder.
The finding, appearing March 1 in the journal Science Immunology, provides a potential new approach to managing symptoms of recurring UTIs that would more effectively target the problem and reduce unnecessary antibiotic usage.
“Urinary tract infections account for almost 25% of infections in women,” said senior author Soman Abraham, Ph.D., professor in the departments of Pathology, Molecular Genetics and Microbiology, Integrative Immunobiology, and Cell Biology at Duke University School of Medicine.
“Many are recurrent UTIs, with patients frequently complaining of chronic pelvic pain and urinary frequency, even after a round of antibiotics,” Abraham said. “Our study, for the first time, describes an underlying cause and identifies a potential new treatment strategy.”
Abraham and colleagues collected bladder biopsies from recurrent UTI patients who were experiencing pain despite no culturable bacteria in their urine. Using biopsies from people without UTIs as a comparison, they found evidence that sensory nerves were highly activated in the UTI patients, explaining the persistent sense of pain and urinary frequency.
Further studies in mice revealed the underlying events, with unique conditions in the bladder that prompt activated nerves in the lining to bloom and grow with each infection.

“Typically, during every bout of UTI, epithelial cells laden with bacteria are sloughed off, and significant destruction of nearby nerve tissue occurs,” said Byron Hayes, lead author of the study and previously a postdoctoral fellow in Duke’s Department of Pathology. “These events trigger a rapid repair program in the damaged bladder involving massive regrowth of destroyed nerve cells.”
This immune response, including repair activities, is led by mast cells — which are immune cells that fight infection and allergens. Mast cells release chemicals called nerve growth factor, which drive overgrowth and increase sensitivity of nerves. The result is pain and urgency.
The researchers were able to address these symptoms by treating study mice with molecules that suppress production of the mast-cell generated nerve growth factor.
“This work helps illuminate a puzzling clinical condition that drives medical costs and affects the quality of life of millions of people, primarily women,” Abraham said. “Understanding the crosstalk between mast cells and nerves is an essential step toward effective treatments for people suffering repeat urinary tract infections.”
In addition to Abraham and Hayes, study authors include Hae Woong Choi, Abhay PS Rathore,Chunjing Bao, Jianling Shi, Yul Huh, Michael W Kim, Andrea Mencarelli, Pradeep Bist, Lai Guan Ng, Changming Shi, Joo Hwan Nho, Aram Kim, Hana Yoon, Donghoon Lim, Johanna L Hannan, J Todd Purves, Francis M Hughes Jr, and Ru-Rong Ji.
The study received funding support from the National Institutes of Health (K12-DK100024, R01-DK121969, R01-DK121032, R01-GM144606), the National Research Foundation of Korea (2020R1C1C1003257), and a Korea University grant.

Image source, Julie BaddockMatthew BassettBBC NewsPublished6 hours agoWhen Alex Baddock’s kidneys failed, his mother did what most parents would do and donated one of hers. But he had to wait until he was three for a transplant, meaning he spent much of his early life on dialysis and needing overnight care.Simply living a normal life was the aim and now, nine years on, 12-year-old Alex and mum Julie, from Ruthin, Denbighshire, are to celebrate their unique bond through one of their passions – skiing. They will take on competitors from around the world on the slopes at the World Transplant Winter Games,

T follicular helper cells (Tfh) are essential for strong antibody-mediated reactions of our immune system during infections and vaccinations. However, if they get out of control, this can cause diseases such as autoimmunity, allergies or cancer. Researchers from the University Hospital Bonn (UKB) and the Cluster of Excellence ImmunoSensation2 at the University of Bonn investigated the underlying mechanisms of Tfh cell development in a mouse model and thus decoded their internal networking. They hope that this will lead to new strategies for the development of highly effective vaccines and new therapies to combat various diseases. The results have now been published in the journal Science Immunology.
T follicular helper cells (Tfh cells) are a specialized subgroup within the so-called CD4+ T helper cells in the immune system. Their main task is to assist the B cells in the immune defense. They are essential for the generation of highly effective antibodies. Tfh cells therefore play a decisive role in protecting against and fighting infections. “Although Tfh cells were first described over 20 years ago, there is still no reliable protocol for their generation in cell culture,” says co-first author Dr. Yinshui Chang, former postdoctoral researcher at the University of Bonn at the UKB, describing the motivation to take a closer look at the process in the mouse model.
The transforming growth factor TGF-β is a cytokine. This is a group of proteins that initiates and regulates the growth and differentiation of cells. The Bonn team led by Prof. Dr. Dirk Baumjohann has now discovered that this signaling molecule induces strong protein expression of both the transcription factor Bcl6 and the chemokine receptor CXCR5, which are characteristic of Tfh cells. The latter plays an important role in the targeted migration of Tfh cells into the vicinity of B cells. “We were able to show that the Tfh cells induced by TGF-β in cell culture are quite similar to the Tfh cells generated in a living organism. They provide crucial help for B cells,” says co-first author Luisa Bach, doctoral student at the University of Bonn at the UKB.
Transcription factor c-Maf controls the fate of T helper cells
Using a new method based on CRISPR gene scissors, the international team led by the Bonn researchers discovered that the production of CXCR5 induced by TGF-β is independent of the transcription factor Bcl6, but requires the transcription factor c-Maf. Remarkably, although Tfh and Th17 cells partially undergo common developmental stages, c-Maf acts as a switching factor for Tfh versus Th17 cell fates. Th17 cells are another special type of CD4+ T helper cells and play an important role in bacterial infections and autoimmune diseases.
“Overall, our data clarify important aspects of the long-unclear prerequisites and molecular pathways for the development of Tfh cells. They also highlight the diverse functions of the transforming growth factor TGF-β. Furthermore, these data indicate that Tfh cell development in mice and humans may not be as different as we previously assumed,” says Prof. Baumjohann from the Medical Clinic III for Hematology, Oncology, Immuno-Oncology and Rheumatology at the UKB, who is a member of the Cluster of Excellence ImmunoSensation2 and the Transdisciplinary Research Area (TRA) “Life & Health” at the University of Bonn. “Importantly, our findings may have implications for the development of new therapeutic strategies that enhance Tfh cells during vaccinations and infections or inhibit them in autoimmune and allergic diseases.”

Results from a new nationwide cohort study show that, despite strong recommendations in favor of consuming omega-3 fatty acids for optimal pregnancy outcomes and offspring health, 25% of participants reported rarely, or never eating fish during pregnancy, with fewer taking omega-3 supplements.
The study, “Demographic and health characteristics associated with fish and n-3 fatty acid supplement intake during pregnancy: results from pregnancy cohorts in the ECHO program” was led by investigators at the Harvard Pilgrim Health Care Institute and published February 27 in Public Health Nutrition. The study is timely, arriving as the World Health Organization and U.S. National Academies both plan to issue reports on the risks and benefits of fish consumption in pregnancy later this year.
“Omega-3 fatty acids are essential nutrients for supporting positive health outcomes. Getting enough of these nutrients during pregnancy is vital for preventing preterm birth and promoting optimal child health and neurodevelopment,” said the study’s lead author Emily Oken, Harvard Medical School professor and chair of the Department of Population Medicine at the Harvard Pilgrim Health Care Institute.
Prior research looking at the demographic characteristics associated with fish and supplement intake during pregnancy has been limited, involving fewer participants and older data that may not represent current intake. The study team addressed this research gap using information on fish consumption reported by 10,800 pregnant women, and supplement intake information from 12,646 pregnant women from cohorts across the U.S. participating in the Environmental influences on Child Health Outcomes (ECHO) program.
Study results showed that nearly 25% of participants reported not eating fish or eating it less than once per month, and only 16% took supplements. Contrary to expectations, supplement use was less common among those who consumed less fish, putting that group at even higher risk for insufficient omega-3 fatty acid intake. Similar to supplement use, older participants with a higher income and education consumed more fish. However, unlike supplements, fish consumption was higher in those with racial/ethnic identities other than non-Hispanic White and in those who used tobacco and nicotine products. The highest likelihood of supplement intake was among those who were older, had a higher education and income, and were non-Hispanic White or Asian. Additionally, supplement use was less common among those at higher risk for adverse pregnancy outcomes as a function of using tobacco or nicotine products or having a higher BMI.
“Current evidence shows that the benefits of maternal consumption of low-mercury fish, or in its place, omega-3 supplements, outweigh any potential risks,” says Dr. Oken. “Our study provides updated information to inform much needed public health advice and resources to support clinical conversations to encourage consumption of low-mercury fish during pregnancy and intake of omega-3 supplements among those who do not consume fish.”

Saint Louis University associate professor of health management and policy in the College for Public Health and Social Justice, SangNam Ahn, Ph.D., recently published a paper in Journal of Clinical Psychology that examines the relationship between childhood adversity, and psychiatric decline as well as adult adversity and psychiatric and cognitive decline. His team discovered that just one instance of adversity in childhood can increase cases of mental illness later in life, and adverse events in adults can lead to a greater chance of both mental illness and cognitive decline later in life.
“Life is very complicated, very dynamic,” Ahn said. “I really wanted to highlight the importance of looking into the lasting health effect of adversity, not only childhood but also adulthood adversity on health outcomes, especially physical health and psychiatric and cognitive health. There have been other studies before, but this is one of the first that looks into these issues comprehensively.”
Ahn, along with his team of researchers, examined data from more nearly 3500 individuals over the course of 24 years. The group took the longitudinal data and evaluated it using a list of lifetime potential traumatic events.
The research team included childhood adversity events such as moving due to financial difficulties, family requiring financial help, a parent experiencing unemployment, trouble with law enforcement before the age of 18, repeating school, physical abuse and parental abuse of drugs or alcohol. Adulthood adversity events included the death of a child, the death of a spouse, experiencing a natural disaster after age 17, firing a weapon in combat, a partner abusing drugs or alcohol, being a victim of a physical attack after age 17, a spouse or child battling a serious illness, receiving Medicaid or food stamps and experiencing unemployment.
The study determined that nearly 40 percent of all individuals experienced a form of childhood adversity, while that number climbed to nearly 80 percent for adulthood adversity. Those who experienced childhood adversity were also 17 percent more likely to experience adulthood adversity. Only 13 percent of individuals sampled reported two or more forms of childhood adversity, while 52 percent of adults experienced two or more forms of adult adversity.
In cases of either childhood adversity or adulthood adversity, researchers found individuals who experienced adversity were also more likely to experience anxiety and depression later in life, and in the case of adulthood adversity, were also more likely to experience cognitive decline later in life.
Individuals with one childhood adversity experience saw a five percent higher chance of suffering from anxiety, and those with two or more childhood adversity experiences had 26 percent and 10 percent higher chances of depression and anxiety, respectively. Individuals who experienced two adulthood adversities had a 24 percent higher chance of depression, while also experiencing a three percent cognitive decline later in life.

While most of the results were expected or unsurprising, one area that stood out to Ahn was education. Those individuals studied who reported higher levels of education saw a reduction in the number of adversity experiences. Ahn hopes to study this avenue more to learn how education may be able to mitigate or prevent these declines.
“Before including education, there was a significant association between childhood adversity and cognitive impairment,” Ahn said. “But when including education as a covariate, that significant association disappeared. Interesting. So there were important implications here. Education and attending school, people could be better off even if they were exposed to childhood adversity. They’re likely to learn positive coping mechanisms, which may help avoid relying on unhealthy coping mechanisms, such as smoking or excessive drinking or drug use.
“Education is quite important in terms of health outcomes,” Ahn added. “If I am educated, I’m likely to get a better job, have a higher income, and live in areas with less crime. I’m likely to buy gym membership or regularly exercise. I’m likely to shop at Whole Foods and get proper nutrition. All of which help combat these adversities we hinted at in the study. So the education and health outcomes are already closely related, and that is what we saw in our study.”
Ahn also encourages clinicians and everyday people alike to discuss their stress. Clinicians can learn more about their patients and have a better approach when it comes to their physical and mental health, while others could potentially relate to shared experiences. But through awareness and recognition, these adverse experiences could potentially have less serious, lasting effects.
“Public health is very interested in stress,” Ahn said. “But we’re still examining how daily stress impacts our long term health outcomes. So to see the effects here in the study, I want people to pay attention to their stress and proactively address it. Clinicians should have deep discussions with their patients about their stress and mental state. And those topics can be approached in other areas too, like the classroom or the dining room table. The more we are aware of stress and discuss our stress, the better we can handle any adversities we find in life.”

Participants in the Framingham Heart Study who achieved higher levels of education tended to age more slowly and went on to live longer lives as compared to those who did not achieve upward educational mobility, according to a new study at Columbia University Mailman School of Public Health and The Robert N. Butler Columbia Aging Center. Upward educational mobility was significantly associated with a slower pace of aging and lower risk of death. The results are published online in JAMA Network Open.
The Framingham Heart Study is an ongoing observational study first initiated in 1948 that currently spans three generations.
The Columbia analysis is the first to connect educational mobility with pace of biological aging and mortality. “We’ve known for a long time that people who have higher levels of education tend to live longer lives. But there are a bunch of challenges in figuring out how that happens and, critically, whether interventions to promote educational attainment will contribute to healthy longevity,” said Daniel Belsky, PhD, associate professor of Epidemiology at Columbia Mailman School and the Aging Center and senior author of the paper.
To measure pace of aging, the researchers applied an algorithm known as the DunedinPACE epigenetic clock to genomic data collected by the Framingham Heart Study. The latest findings showed that, according to the yardstick of the DunedinPACE epigenetic clock, two years of additional schooling translated to a two- to three percent slower pace of aging. This slowing in the pace of aging corresponds to a roughly 10 percent reduction in risk of mortality in the Framingham Heart Study, according to previous research by Belsky on the association of DunedinPACE with risk of death.
DunedinPACE was developed by the Columbia researchers and colleagues and reported in January 2022. Based on an analysis of chemical tags on the DNA contained in white blood cells, or DNA methylation marks, DunedinPACE is named after the Dunedin Study birth cohort used to develop it. DunedinPACE (stands for Pace of Aging Computed from the Epigenome), is measured from a blood test and functions like a speedometer for the aging process, measuring how fast or slow a person’s body is changing as they grow older.
Biological aging refers to the accumulation of molecular changes that progressively undermine the integrity and resilience capacity of our cells, tissues and organs as we grow older.
The Columbia researchers used data from 14,106 Framingham Heart Study spanning three generations to link children’s educational attainment data with that of their parents. They then used data from a subset of participants who provided blood samples during data collection to calculate the pace of biological aging using the DunedinPACE epigenetic clock. In primary analysis, the researchers tested associations between educational mobility, aging, and mortality in a subset of 3,101 participants for whom educational mobility and pace of aging measures could be calculated.

For 2,437 participants with a sibling, the researchers also tested whether differences in educational attainment between siblings was associated with a difference in the pace of aging.
“A key confound in studies like these is that people with different levels of education tend to come from families with different educational backgrounds and different levels of other resources,” explained Gloria Graf, a PhD candidate in the Department of Epidemiology supervised by Belsky, and first author of the study. “To address these confounds, we focused on educational mobility, how much more (or less) education a person completed relative to their parents, and sibling differences in educational attainment — how much more (or less) education a person completed relative to their siblings. These study designs control for differences between families and allow us to isolate the effects of education.”
By combining these study designs with the new DunedinPACE epigenetic clock, the researchers were able to test how education affects the pace of aging. Then, by linking the education and pace of aging data with longitudinal records of how long participants lived, the team was able to determine if a slower pace of aging accounted for increased longevity in people with more education.
“Our findings support the hypothesis that interventions to promote educational attainment will slow the pace of biological aging and promote longevity,” noted Graf. “Ultimately, experimental evidence is needed to confirm our findings,” added Belsky. “Epigenetic clocks like DunedinPace have potential to enhance such experimental studies by providing an outcome that can reflect impacts of education on healthy aging well before the onset of disease and disability in later life.”
“We found that upward educational mobility was associated both with a slower pace of aging and decreased risk of death,” said Graf. “In fact, up to half of the educational gradient in mortality we observed was explained by healthier aging trajectories among better-educated participants.” This pattern of association was similar across generations and held within family sibling comparisons: siblings with higher educational mobility tended to have a slower pace of aging as compared with their less educated siblings.
Co-authors are Calen Ryan, Meeraj Kothari, and Alison Aiello, Columbia Mailman School of Public Health and Butler Columbia Aging Center; Peter Muennig, Columbia Mailman School of Public Health; Terrie Moffitt, Avshalom Caspi, and Karen Sugden, Duke University; and Hexuan Liu, University of Cincinnati.
The study was supported by the National Institutes of Health, grants R01AG073402, R01AG073207, and R21AG078627.

Researchers at the National Institutes of Health have identified antibodies targeting a hard-to-spot region of the influenza virus, shedding light on the relatively unexplored “dark side” of the neuraminidase (NA) protein head. The antibodies target a region of the NA protein that is common among many influenza viruses, including H3N2 subtype viruses, and could be a new target for countermeasures. The research, led by scientists at the National Institute of Allergy and Infectious Diseases’ Vaccine Research Center, part of NIH, was published today in Immunity.
Influenza, or flu, sickens millions of people across the globe each year and can lead to severe illness and death. While vaccination against influenza reduces the burden of the disease, updated vaccines are needed each season to provide protection against the many strains and subtypes of the rapidly evolving virus. Vaccines that provide protection against a broad range of influenza viruses could prevent outbreaks of new and reemerging flu viruses without the need for yearly vaccine reformulation or vaccinations.
One way to improve influenza vaccines and other countermeasures is to identify new targets on the virus’s surface proteins in “conserved” regions — portions that tend to be relatively unchanged between different strains of the virus. Influenza NA is a surface protein containing a globular head portion and a narrow stalk portion. The underside of the NA head contains a highly conserved region with targets for antibodies — known as epitopes — that make it vulnerable to antibody binding and inhibition of the virus, as well as not being impacted by mutations common in drug-resistant strains. This region is termed the “dark side” due to its partially hidden location and relatively unexplored characteristics.
The researchers isolated human antibodies that target the NA dark side from the blood of two people who had recovered from influenza type A subtype H3N2, a major subtype of seasonal flu viruses. In lab tests, the antibodies inhibited propagation of viruses from subtype H2N2, the subtype that caused pandemic influenza in 1957-58, and H3N2 viruses from humans, swine, and birds. The antibodies also protected mice from lethal infection by a subtype H3N2 virus when given to the animals either one day before or two days after infection, showing that the antibody may treat and prevent influenza in this model.
The scientists analyzed the structure of two of the antibodies while bound to NA using advanced microscopy techniques known as cryogenic electron microscopy. Each antibody targeted different, nonoverlapping regions of the dark side, demonstrating that this region has multiple areas that may be useful to explore for countermeasure development.
These findings show that the NA dark side has unique, previously untapped epitopes that could be applied to the development of new vaccine and therapeutic strategies. They suggest that antibodies targeting the NA dark side could be useful in combination with antivirals or other types of antibodies for interventions against influenza, as they are effective against influenza viruses with drug-resistant mutations. The researchers also note that NA dark side targets could be included in the next generation of broadly protective vaccines against influenza.

Early riser or night owl, everyone appreciates a good night’s sleep. But despite the best of intentions, quality sleep can elude us, sometimes to the point where it can contribute to serious health issues.
Now, a world first study from the University of South Australia shows that getting a good night’s sleep is tied to how you structure your day, with exercise at the heart of sleep quality.
The study examined different components of time use and different aspects of sleep among 1168 children (average age 12 years) and 1360 adults (their parents, average age 44 years, mainly mothers) the study found that children and adults with higher levels of moderate to vigorous physical activity had less troubled sleep, reduced tiredness, and better sleep quality.
Australian guidelines indicate that most adults need about eight hours of sleep per night, with children and teenagers requiring 8-11 hours per night.*
UniSA researcher, Dr Lisa Matricciani, says understanding factors that affect sleep quality is vital for good health and wellbeing.
“Despite what we know about sleep, many people still struggle to achieve a good night’s sleep,” Dr Matricciani says.
“When people think about sleep quality, they tend to focus on adjustments immediately before bedtime — for example, avoiding screens, not eating too much, and avoiding alcohol — but our research looks beyond this to the range of activities we undertake during the day.

“What we found is that our daytime activities are tied to different aspects of our sleep, from sleep quality, sleep efficiency (how much of the time you spend in bed when you are actually asleep), and the overall amount of sleep we get, to levels of tiredness during the day, and when we choose to go to bed.
“Sometimes, the activities we choose might directly displace sleep — think of kids playing video games late into the night — but other times, it’s how we spend our daytime hours.
“In this study we created different simulations to see how extending and restricting aspects of time were related to different aspects of sleep.
“We found that if children and adults increased moderate to vigorous physical activity, they would feel less tired, have less troubled sleep and better-quality sleep.
“Interestingly, simply making more time for sleep predicted more restless sleep.
“Everyone wants a good night’s sleep. If it’s simply a matter of being more active during the day, then it may be a relatively achievable goal for most of us.”

New findings reveal that the body undergoes significant, systematic changes across multiple organs during prolonged periods of fasting. The results demonstrate evidence of health benefits beyond weight loss, but also show that any potentially health-altering changes appear to occur only after three days without food.
The study, published today in Nature Metabolism, advances our understanding of what’s happening across the body after prolonged periods without food.
By identifying the potential health benefits from fasting and their underlying molecular basis, researchers from Queen Mary University of London’s Precision Healthcare University Research Institute (PHURI) and the Norwegian School of Sports Sciences provide a road map for future research that could lead to therapeutic interventions — including for people that may benefit from fasting but cannot undergo prolonged fasting or fasting-mimicking, such as ketogenic, diets.
Over millennia, humans have developed the ability to survive without food for prolonged periods of time. Fasting is practiced by millions of people throughout the world for different medical and cultural purposes, including health benefits and weight loss. Since ancient times, it has been used to treat diseases such as epilepsy and rheumatoid arthritis.
During fasting, the body changes its source and type of energy, switching from consumed calories to using its own fat stores. However, beyond this change in fuel sources, little is known about how the body responds to prolonged periods without food and any health impacts — beneficial or adverse — this may have. New techniques allowing researchers to measure thousands of proteins circulating in our blood provide the opportunity to systematically study molecular adaptions to fasting in humans in great detail.
Researchers followed 12 healthy volunteers taking part in a seven-day water-only fast. The volunteers were monitored closely on a daily basis to record changes in the levels of around 3,000 proteins in their blood before, during, and after the fast. By identifying which proteins are involved in the body’s response, the researchers could then predict potential health outcomes of prolonged fasting by integrating genetic information from large-scale studies.
As expected, the researchers observed the body switching energy sources — from glucose to fat stored in the body — within the first two or three days of fasting. The volunteers lost an average of 5.7 kg of both fat mass and lean mass. After three days of eating after fasting, the weight stayed off — the loss of lean was almost completely reversed, but the fat mass stayed off.

For the first time, the researchers observed the body undergoing distinct changes in protein levels after about three days of fasting — indicating a whole-body response to complete calorie restriction. Overall, one in three of the proteins measured changed significantly during fasting across all major organs. These changes were consistent across the volunteers, but there were signatures distinctive to fasting that went beyond weight loss, such as changes in proteins that make up the supportive structure for neurons in the brain.
Claudia Langenberg, Director of Queen Mary’s Precision Health University Research Institute (PHURI), said:
“For the first time, we’re able to see what’s happening on a molecular level across the body when we fast. Fasting, when done safely, is an effective weight loss intervention. Popular diets that incorporate fasting — such as intermittent fasting — claim to have health benefits beyond weight loss. Our results provide evidence for the health benefits of fasting beyond weight loss, but these were only visible after three days of total caloric restriction — later than we previously thought.”
Maik Pietzner, Health Data Chair of PHURI and co-lead of the Computational Medicine Group at Berlin Institute of Health at Charité, said:
“Our findings have provided a basis for some age-old knowledge as to why fasting is used for certain conditions. While fasting may be beneficial for treating some conditions, often times, fasting won’t be an option to patients suffering from ill health. We hope that these findings can provide information about why fasting is beneficial in certain cases, which can then be used to develop treatments that patients are able to do.”

Proteins not only carry out the functions that are critical for the survival of cells, but also influence the development and progression of diseases. To understand their role in health and disease, researchers study the three-dimensional atomic structure of proteins using both experimental and computational methods.
Over 75 percent of proteins present at the surface of our cells are covered by glycans. These sugar-like molecules form very dynamic protective shields around the proteins. However, the mobility and variability of the sugars make it difficult to determine how these shields behave, or how they influence the binding of drug molecules.
Mateusz Sikora, the project leader and head of the Dioscuri Centre for Modelling of Posttranslational Modifications, and his team in Krakow and partners at the Max Planck Institute of Biophysics in Frankfurt am Main, Germany, have addressed this challenge by using computers, working together with scientists at Inserm in Paris, Academia Sinica in Tapei and the University of Bremen. Their powerful new algorithm GlycoSHIELD enables a fast but realistic modeling of the sugar chains present on protein surfaces. Reducing computing hours and therefore power consumption by several orders of magnitude compared to conventional simulation tools, GlycoSHIELD paves the path towards green computing.
From thousands of hours to a few minutes
Protective glycan shields strongly influence how proteins interact with other molecules such as therapeutic drugs. For example, the sugar layer on the spike protein of the coronavirus hides the virus from the immune system by making it difficult for natural or vaccine-induced antibodies to recognize the virus. The sugar shields therefore play an important role in drug and vaccine development. Pharmaceutical research could benefit from routinely predicting their morphology and dynamics. Until now, however, forecasting the structure of sugar layers using computer simulations was only possible with expert knowledge on special supercomputers. In many cases, thousands or even millions of computing hours were required.
With GlycoSHIELD, Sikora’s team provides a fast, environmentally friendly open source alternative. “Our approach reduces resources, computing time and the technical expertise needed,” says Sikora. “Anyone can now calculate the arrangement and dynamics of sugar molecules on proteins on their personal computer within minutes, without the need of expert knowledge and high-performance computers. Furthermore, this new way of making calculations is very energy efficient.” The software can not only be used in research, but could also be helpful for the development of drugs or vaccines, for example in immunotherapy for cancer.
A jigsaw puzzle made of sugar
How did the team manage to achieve such a high increase in efficiency? The authors created and analyzed a library of thousands of most likely 3D poses of the most common forms of sugar chains on proteins found in humans and microorganisms. Using long simulations and experiments, they found that for a reliable prediction of glycan shields, it is sufficient that the attached sugars do not collide with membranes or parts of the protein.
The algorithm is based on these findings. “GlyoSHIELD users only have to specify the protein and the locations where the sugars are attached. Our software then puzzles them on the protein surface in the most likely arrangement,” explains Sikora. “We could reproduce the sugar shields of the spike protein accurately: they look exactly as what we see in the experiments!” With GlycoSHIELD it is now possible to supplement new as well as existing protein structures with sugar information. The scientists also used GlycoSHIELD to reveal the pattern of the sugars on the GABAA receptor, an important target for sedatives and anesthetics.