Publisher Health

An interdisciplinary team of researchers from the University of Missouri, Children’s Mercy Kansas City and Texas Children’s Hospital has used a new data-driven approach to learn more about persons with Type 1 diabetes, who account for about 5-10% of all diabetes diagnoses. The team gathered its information through health informatics and applied artificial intelligence (AI) to better understand the disease.
In the study, the team analyzed publicly available, real-world data from about 16,000 participants enrolled in the T1D Exchange Clinic Registry.By applying a contrast pattern mining algorithm developed at the MU College of Engineering, the team was able to identify major differences in health outcomes among people living with Type 1 diabetes who do or do not have an immediate family history of the disease.
Chi-Ren Shyu, the director of the MU Institute for Data Science and Informatics (MUIDSI), led the AI approach used in the study, and said the technique is exploratory in nature.
“Here we let the computer do the work of connecting millions of dots in the data to identify only major contrasting patterns between individuals with and without a family history of Type 1 diabetes, and to do the statistical testing to make sure we are confident in our results,” said Shyu, the Paul K. and Dianne Shumaker Professor in the MU College of Engineering.
Erin Tallon, a graduate student in the MUIDSI and the lead author on the study, said the team’s analysis resulted in some unfamiliar findings.
“For instance, we found individuals in the registry who had an immediate family member with Type 1 diabetes were more frequently diagnosed with hypertension, as well as diabetes-related nerve disease, eye disease and kidney disease,” Tallon said. “We also found a more frequent co-occurrence of these conditions in individuals who had an immediate family history of Type 1 diabetes. Additionally, individuals who had an immediate family history of Type 1 diabetes also more frequently had certain demographic characteristics.”
Tallon’s passion for this project began with a personal connection, and quickly grew as a result of her experience working as a nurse in an intensive critical care unit (ICU). She would often see patients with Type 1 diabetes who were also dealing with other co-existing conditions such as kidney disease and high blood pressure. Knowing that a person’s Type 1 diabetes diagnosis often occurs only when the disease is already very advanced, she wanted to find better ways for prevention and diagnosis, starting with finding a way to analyze the large amounts of publicly available data already collected about the disease.

DNA is often likened to a blueprint. The particular sequence of As, Cs, Gs, and Ts in DNA provides information for building an organism.
What’s not captured by this analogy is the fact that our DNA requires constant upkeep to maintain its integrity. Were it not for dedicated DNA repair machinery that routinely fixes mistakes, the information within DNA would be rapidly degraded.
This repair happens at cell cycle checkpoints that are activated in response to DNA damage. Like a quality assurance agent on an assembly line, proteins that participate in the DNA damage checkpoint assess the cell’s DNA for mistakes and, if necessary, pause cell division and make repairs. When this checkpoint breaks down — which can happen as a result of genetic mutations — DNA damage builds up, and the result is often cancer.
Though scientists have learned much about DNA damage and repair over the past 50 years, important outstanding questions remain. One particularly bedeviling puzzle is how a repair protein called the 9-1-1 clamp — a DNA damage “first responder” — attaches itself to the site of a broken DNA strand to activate of the DNA damage checkpoint.
“We know that this attachment is a pivotal step necessary for initiating an effective repair program,” says Dirk Remus, a molecular biologist at the Sloan Kettering Institute (SKI) who studies the fundamentals of DNA replication and repair. “But the mechanisms involved are completely obscure.”
Now, thanks to a collaboration between Dr. Remus’ lab and that of SKI structural biologist Richard Hite, a clear picture of how the 9-1-1 clamp is recruited to sites of DNA damage has emerged. The results, which challenge conventional wisdom in the field, were published March 21, 2022, in the journal Nature Structural and Molecular Biology.

Researchers from Indiana University School of Medicine Department of Microbiology and Immunology are studying new ways to treat seasonal or intermittent asthma. Their findings were recently published in Science Immunology.
“Asthma has no cure and current treatments primarily focus on resolving the symptoms,” said Ben Ulrich, PhD, lead author of the study. “While spending time in the high-risk asthma clinic at Riley Hospital for Children, I observed many patients had a more intermittent disease course. We went into the lab and developed models to more accurately define allergic memory and recall response in the lung.”
When someone with seasonal or intermittent asthma breathes in allergens, they can have symptoms such as wheezing, coughing and, in severe cases, asthmatic exacerbation or hospitalization. These symptoms result from inflammation, airway constriction, and mucus production. Once exposed to the seasonal allergens, which include exposure to pollens, fungi or other allergens only prevalent at certain times of the year, antigen-presenting cells activate CD4 positive T-cells to secrete cytokines, starting inflammatory cascades. The team looked at one cytokine, called interleukin 9 (IL-9), to see how it impacts allergic memory responses.
They found a unique population of memory CD4 T-cells that produced IL-9, along with IL-5 and IL-13. These cells secreted IL-9 in an antigen-specific manner. Additionally, these cells express ST2, which is an IL-33 receptor, and demonstrated amplified IL-9 production in the presence of IL-33 in an allergen-specific manner. Blockade of IL-9 led to a decrease in expression of several genes associated with mucus production in the epithelial cells. It also led to a decrease in CD4 T-cells and B-cells and altered expression of activation markers on microphages.
“Asthma exists in multiple forms and seasonal or intermittent asthma can be very different from other forms because of chronic exposure to allergens,” said Mark Kaplan, PhD, chair of the IU School of Medicine Department of Microbiology and Immunology and senior author of the study. “This study demonstrates targeting IL-9 in the lungs during seasonal allergies could help with lung inflammation. By focusing on a population of memory cells that mediate the allergic recall responses of the lungs, we could develop new targets for treatments.”
Other major collaborators include Rakshin Kharwadkar, PhD (now at Genentech), Michelle Chu and Abigail Pajulas. Other faculty authors from IU School of Medicine include Amelia Linnemann, PhD, Matthew Turner, PhD, MD and Yunlong Liu, PhD. Other collaborators include investigators at University of Virginia, Yale University, Mayo Clinic and Universidad Nacional Autónoma de México.
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Materials provided by Indiana University School of Medicine. Original written by Christina Griffiths. Note: Content may be edited for style and length.

It’s not easy to be sure that drugs and supplements with twisted — or chiral — structures are turning in the correct direction. Now, twirling infrared light can probe both the structures of molecular crystals and their twists, research led by the University of Michigan has shown.
The researchers hope that the technique could also help diagnose harmful accumulations of twisted molecules in the body, including bladder stones, insulin fibrils and amyloid aggregations such as the plaques that appear in Alzheimer’s disease.
In a world of curled molecules, biology often favors right- or left-handed versions. Walking along the supplement aisle, you might notice that some have an L or D in front of the names. L and D denote the direction in which the molecule twists, clockwise or counterclockwise — the human body typically only uses one version. Molecules with the wrong twist can be nuisance fillers or cause side effects that can be unpleasant or dangerous. But quality control for twisted molecules is tough, and monitoring the chiral structures of drugs and supplements kept in storage isn’t usually done.
“The methods most commonly used at pharmaceutical companies are very sensitive to impurities, but measuring chirality is expensive,” said Wonjin Choi, a research fellow in chemical engineering at U-M and first author of the paper in Nature Photonics.
The new method can quickly recognize wrong twists and wrong chemical structures in packaged drugs using terahertz radiation, a portion of the infrared part of the spectrum. It was developed by an international team, including researchers at the Federal University of São Carlos, Brazil; Brazilian Biorenewables National Laboratory; University of Notre Dame; and Michigan State University.
“Biomolecules support twisting, long-range vibrations also known as chiral phonons. These vibrations are very sensitive to the structure of molecules and their nanoscale assemblies, creating the fingerprint of a particular chiral structure,” said Nicholas Kotov, the Irving Langmuir Distinguished University Professor of Chemical Sciences and Engineering at U-M and co-corresponding author.

A new computational approach developed by researchers at The University of Texas MD Anderson Cancer Center successfully combines data from parallel gene-expression profiling methods to create spatial maps of a given tissue at single-cell resolution. The resulting maps can provide unique biological insights into the cancer microenvironment and many other tissue types.
The study was published today in Nature Biotechnology and will be presented at the upcoming American Association for Cancer Research (AACR) Annual Meeting 2022 (Abstract 2129).
The tool, called CellTrek, uses data from single-cell RNA sequencing (scRNA-seq) together with that of spatial transcriptomics (ST) assays — which measure spatial gene expression in many small groups of cells — to accurately pinpoint the location of individual cell types within a tissue. The researchers presented findings from analysis of kidney and brain tissues as well as samples of ductal carcincoma in situ (DCIS) breast cancer.
“Single-cell RNA sequencing provides tremendous information about the cells within a tissue, but, ultimately, you want to know where these cells are distributed, particularly in tumor samples,” said senior author Nicholas Navin, Ph.D., professor of Genetics and Bioinformatics & Computational Biology. “This tool allows us to answer that question with an unbiased approach that improves upon currently available spatial mapping techniques.”
Single-cell RNA sequencing is an established method to analyze the gene expression of many individual cells from a sample, but it cannot provide information on the location of cells within a tissue. On the other hand, ST assays can measure spatial gene expression by analyzing many small groups of cells across a tissue but are not capable of providing single-cell resolution.
Current computational approaches, known as deconvolution techniques, can identify different cell types present from ST data, but they are not capable of providing detailed information at the single-cell level, Navin explained.
Therefore, co-first authors Runmin Wei, Ph.D., and Siyuan He of the Navin Laboratory led the efforts to develop CellTrek as a tool to combine the unique advantages of scRNA-seq and ST assays and create accurate spatial maps of tissue samples.
Using publicly available scRNA-seq and ST data from brain and kidney tissues, the researchers demonstrated that CellTrek achieved the most accurate and detailed spatial resolution of the methods evaluated. The CellTrek approach also was able to distinguish subtle gene expression differences within the same cell type to gain information on their heterogeneity within a sample.
The researchers also collaborated with Savitri Krishnamurthy, M.D., professor of Pathology, to apply CellTrek to study DCIS breast cancer tissues. In an analysis of 6,800 single cells and 1,500 ST regions from a single DCIS sample, the team learned that different subgroups of tumor cells were evolving in unique patterns within specific regions of the tumor. Analysis of a second DCIS sample demonstrated the ability of CellTrek to reconstruct the spatial tumor-immune microenvironment within a tumor tissue.
“While this approach is not restricted to analyzing tumor tissues, there are obvious applications for better understanding cancer,” Navin said. “Pathology really drives cancer diagnoses and, with this tool, we’re able to map molecular data on top of pathological data to allow even deeper classifications of tumors and to better guide treatment approaches.”
This research was supported by the National Institutes of Health/National Cancer Institute (RO1CA240526, RO1CA236864, CA016672), the Cancer Prevention and Research Institute of Texas (CPRIT) (RP180684), the Chan Zuckerberg Initiative SEED Network Grant, and the PRECISION Cancer Grand Challenges Grant. Navin is supported by the American Association for the Advancement of Science (AAAS) Martin and Rose Wachtel Cancer Research Award, the Damon Runyon-Rachleff Innovation Award, the Andrew Sabin Family Fellowship, and the Jack and Beverly Randall Prize for Excellence in Cancer Research. Wei is supported by a Damon Runyon Quantitative Biology Fellowship Award.
Collaborating MD Anderson authors include Shanshan Bai, Emi Sei, Ph.D., and Min Hu, all of Genetics; and Ken Chen, Ph.D., of Bioinformatics. Additional authors include Alastair Thompson, M.D., of Baylor College of Medicine, Houston. The authors have no conflicts of interest.

Research from the Francis Crick Institute has revealed a key mechanism which increases tolerance to drugs amongst microbial communities. The findings could help the development of more effective antifungal treatments.
Antimicrobial drug resistance and tolerance occurs when bacteria, viruses, fungi or parasites no longer respond, or have less sensitivity, to treatments. It is a major issue within medicine, for example, invasive fungal infections are responsible for 1.6 million deaths annually.
“Around the world, more people die each year from invasive fungal species than from malaria. There are currently only three classes of antifungal drugs in clinical use and in an increasing number of cases, these antifungals fail. Understanding the mechanisms which increase or decrease the chance of a drug working is crucial to aid the developments of new treatments,” explains Jason Yu, co-first author and postdoctoral training fellow in the Molecular Biology of Metabolism Laboratory at the Crick.
In their study, published in Nature Microbiology today (Monday 21 March), the scientists analysed data from 12,000 microbial communities from all over the world, provided by the Earth Microbiome Project.
Within these groups of different microorganisms, which live together producing and absorbing materials they all need to survive and grow, the researchers found one type in particular was highly prevalent. Auxotrophs, which are unable to create essential metabolites, like amino acids, vitamins or fatty acids, were present in 99.95% of the 12,538 communities they studied.
Clara Correia-Melo, co-first author and researcher in the Molecular Biology of Metabolism Laboratory at the Crick and the Department of Biochemistry at University of Cambridge, says: “The widespread nature of auxotrophs has been considered a paradox, a fundamental problem in our understanding of microbiology. This is because they must absorb metabolites from the environment and so they have been thought of as weaker than other cells which can create these chemical compounds themselves. They have been seen as scrounger cells, a drain on communal resources.”
By analysing drug exposure data from the project, the scientists found that communities with auxotrophs are more likely to have tolerance against hundreds of drugs, than communities without these cells. Moreover, the research showed that they are not scrounger cells, but rather cooperative partners as, in exchange for taking up metabolites that are essential for them, they return other metabolites to the community.
Further experiments using a yeast model showed that this increased tolerance is because cells that cooperate in metabolism, have increased levels of metabolic export, the movement of metabolites out of cells. As a side-effect, this also causes drugs to be moved out of cells at a higher rate.
Clara Correia-Melo adds: “This work solves a paradox around auxotroph success by revealing how auxotrophs are very valuable to their communities. They increase the metabolic interactions within the communities, and by doing so, increase the tolerance to drugs. Additionally, the increase in metabolic flow also leads to an enrichment of the shared environment, with more supplies available that can be used for growth and survival.”
Markus Ralser, senior author and group leader of the Molecular Biology of Metabolism Laboratory at the Crick and head of the Institute of Biochemistry at Charité, a leading university hospital in Berlin adds: “Our observations go beyond microbial ecology, they open a whole field of research exploring the contribution of metabolism and the metabolic environment to antimicrobial resistance.
“We hope that this will allow the design of new generations of antifungals, that target not only cell growth but also tolerance, and hence will be more effective than the currently available treatments.”
The researchers will continue this work, collecting clinically relevant fungal species and analysing their response to antimicrobials.

When something goes wrong during DNA replication, cells call their own version of 911 to pause the process and fix the problem — a failsafe that is critical to maintaining health and staving off disease.
Now, scientists at Van Andel Institute and The Rockefeller University have for the first time revealed how a key piece of this repair process — appropriately called the 911 DNA checkpoint clamp — is recruited to the site of DNA damage. The findings, published today in Nature Structural and Molecular Biology,illuminate new insights into the way cells ensure genetic instructions are properly passed from one generation of cells to the next. The project was led by the study’s co-corresponding authors Huilin Li, Ph.D., of VAI, and Michael E. O’Donnell, Ph.D., of The Rockefeller University and Howard Hughes Medical Institute.
“DNA damage can have severe consequences, including cancer and other diseases. Because of this, our cells have a host of checks and balances to ensure DNA integrity,” Li said. “Our high-resolution structure of the 911 DNA checkpoint clamp as it interacts with the molecule that loads it onto the DNA strand gives us a detailed look at the essential process of DNA repair. We hope these insights can be leveraged toward the development of new therapeutic strategies for diseases linked to DNA damage.”
Each day, billions of cells in the human body are replaced through cell division, a process by which one cell splits into two. This fundamental function drives growth and facilitates maintenance of tissues such as skin and muscle. A central part of this system is DNA replication, in which our genetic instruction manual is carefully replicated to ensure each cell has an accurate copy.
DNA damage can result from mistakes in this process or through other factors that directly harm DNA, such as exposure to UV light from the sun or carcinogens such as tobacco smoke. When damage occurs, cells have emergency response systems to either stop replication until the problem can be repaired or to kill the cell, thus preventing the incorrect information from being passed on.
This is where the 911 DNA checkpoint clamp comes in. When DNA damage is detected, the ring-shaped clamp is loaded on the DNA and transported to the site of the error. Once there, it sends a signal to halt cell division while also flagging other repair molecules to remove the damaged DNA and replace it with a corrected sequence.
The structure was determined through use of VAI’s cryo-electron microscopes (cryo-EM), which allow scientists to visualize molecular structures at the atomic level. In the case of the 911 DNA checkpoint clamp, cryo-EM also revealed a surprise: rather than loading onto DNA from the 3′ (or “three prime”) end like all other known DNA clamps, the 911 clamp is loaded onto DNA from the opposite end, called the 5′ (“five prime”) end. This novel and unexpected finding reshapes what we know about DNA replication and sets the stage for further studies in this area.
Other study authors are Fengwei Zheng, Ph.D., of VAI; and Roxana E. Georgescu, Ph.D., and Nina Y. Yao, Ph.D., of The Rockefeller University. Cryo-EM data were collected in collaboration with VAI’s Cryo-EM Core and the David Van Andel Advanced Cryo-Electron Microscopy Suite.
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Materials provided by Van Andel Research Institute. Note: Content may be edited for style and length.

According to estimates by the World Health Organization (WHO), between six and seven million people worldwide, predominantly in Central and South America, are infected with the Trypanosoma cruzi species of trypanosome. This single-celled (protozoan) parasite causes Chagas disease (American trypanosomiasis), which in the acute phase is inconspicuous: only in every third case does the infected person develop any symptoms at all, which can then be unspecific, such as fever, hives and swollen lymph nodes. However, the parasites remain in the body, and many years later chronic Chagas disease can become life-threatening, with pathological enlargement of the heart and progressive paralysis of the gastrointestinal tract.
There is no vaccine against the pathogen and treating the disease in the advanced stage is difficult. That is why the focus in Latin America is rather on controlling the bug that transmits Chagas trypanosomes: the predatory blood-sucking bug of the insect subfamily Triatominae. It ingests the trypanosomes during the sting, which then colonize its intestine. Through its faeces that it mostly deposited next to the bite, the bug excretes the pathogen, which is often rubbed into the wound when scratching the extremely itchy bite.
Although the number of new infections has dropped in various regions where insecticides are sprayed on a wide scale, problems are emerging: over the last decade, resistance to common insecticides by several species of predatory bugs has been increasingly observed. These insecticides also have a negative impact on the environment and the local population.
Researchers worldwide are making intense efforts to find alternative methods to help control Trypanosoma cruzi. One possibility might be to modify bacteria in the predatory bug’s intestine in such a way that they eliminate the Chagas trypanosomes or inhibit their development.
In collaboration with scientists at the Instituto René Rachou in Belo Horizonte, Brazil, parasitologists and infection biologists Fanny Eberhard and Professor Sven Klimpel from Goethe University, the Senckenberg — Leibniz Institution for Biodiversity and Earth System Research (SGN) and the LOEWE Centre for Translational Biodiversity Genomics have now investigated how Chagas trypanosomes change the bacterial community in the predatory bug’s intestine. To do so, they used genome analysis, which allowed them to compare the composition of the bacterial community in the bug’s intestine, the microbiome, before and after infection with the pathogen (metagenomic shotgun sequencing).
The result: after the infection, the range of bacterial strains in the bug’s intestine significantly decreased. Certain strains, including the potentially pathogenic bacterium Enterococcus faecalis, profited from the parasites’ presence. Moreover, the researchers succeeded in identifying four bacterial species that probably take on functions important for the bug, such as the synthesis of B vitamins.
Fanny Eberhard explains: “Vitamin B is one of the nutrients that blood-sucking insects do not obtain through their blood meals. Bacteria that produce vitamin B are therefore very important for the bug, are found in practically all individuals and stay in the predatory bug’s intestine even across generations. Hence, such bacteria are potentially suitable recipients for genes that produce defensive substances against Chagas trypanosomes.”
Professor Sven Klimpel elaborates: “Ultimately, our goal is for the predatory bug to defend itself against Chagas trypanosomes and, in this way, to prevent infection in humans. However, before we can produce bacteria with such properties and then release predatory bugs containing them, we need to understand better how the ecology of the bug’s intestine is structured and how the extensive interactions between host, pathogen and microbiome function. Our work is delivering an essential contribution to this.”
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Materials provided by Goethe University Frankfurt. Note: Content may be edited for style and length.

Meningiomas, tumors of the membranes (meninges) surrounding the brain and spinal cord, are the most common tumors of the central nervous system. Although most meningiomas are low grade and cause few or no symptoms, a subset, called high-grade meningiomas, can cause serious neurologic and cognitive problems and have high mortality rates.
Meningiomas are treated with surgery and in some cases radiation, but there are few other effective therapies, and even with optimal therapy, recurrences are common: About half of all patients with intermediate (grade 2) meningiomas will have a recurrence within 5 years of treatment, and 90% of patients with the most advanced (grade 3) meningiomas will experience recurrences within 5 years.
Only about half of all patients with recurrent aggressive grade 2 meningiomas and none with grade 3 disease can be expected to survive for 10 years.
But as Priscilla Brastianos, MD, from the Mass General Cancer Center and Harvard Medical School (HMS) and colleagues now report, a class of cancer drugs known as immune checkpoint inhibitors can slow disease progression and offer hope for longer survival of patients with high-grade meningiomas.
They report their findings in the open-access journal Nature Communications.
“In the past our understanding of the molecular underpinnings of meningiomas has been limited, and it has only been within the last few years that we have begun to understand the immune microenvironment of meningiomas,” says Brastianos.

Scientists have found that a predatory bacterium, capable of invading and consuming harmful bugs such as E.coli and Salmonella, can sculpt its own shape to fit inside its prey.
In a new paper, published in Nature Communications today, scientists from the Universities of Nottingham, Birmingham and Newcastle, showed that the curved (boomerang-like) shape of the bacterium, called Bdellovibrio bacteriovorus, is an important feature that affects its lifestyle, enabling it to efficiently invade, grow and live inside other bacteria.
The team also found that a bacterial cell-wall-modifying gene has unique features that enable the bacteria to sculpt its own distinctive shape.
The researchers previously discovered how the bacterium is able to invade prey cells, without harming themselves, by sculpting prey into a sphere shape using proteins that the Bdellovibrio secrete to change the prey’s cell walls.
This spherical space inside the prey becomes a home in which the Bdellovibrio use the prey as food and grow and develop into cells shaped like a curved string of boomerang shaped sausages. These separate, and then escape and find more prey.
Bdellovibrio bacteriovorus can be isolated from soil and water around the world and each isolate has the curved shape but its hasn’t been fully understood why and how they are shaped like this. In this new paper, the researchers found that the curved boomerang shape of the Bdellovibrio, is produced by a special protein — Bd1075 — that the Bdellovibrio uses on itself (rather than secreting into prey). Without this protein the curved shape is lost.