A University of Houston researcher is reporting a new method to detect cancer which could make cancer detection as simple as taking a blood test. With a 98.7% accuracy rate, the method — which combines PANORAMA imaging with fluorescent imaging — has the potential to detect cancer at the earliest stage and improve treatment efficacy.
The remarkably precise method allows researchers to peer into nanometer-sized membrane sacs, called extracellular vesicles or EVs, that can carry different types of cargos, like proteins, nucleic acids and metabolites, in the bloodstream.
When Wei-Chuan Shih, Cullen College of Engineering professor of electrical and computer engineering, and his team examined the number and cargo of small EVs inside patients with cancer and those without, their finding was remarkable.
“We observed differences in small EV numbers and cargo in samples taken from healthy people versus people with cancer and are able to differentiate these two populations based on our analysis of the small EVs,” reports Shih, in Nature Communications Medicine. “The findings came from combining two imaging methods — our previously developed method PANORAMA and imaging of fluorescence emitted by small EVs — to visualize and count small EVs, determine their size and analyze their cargo.”
In 2020, Shih debuted the PANAROMA optical imaging technology, which uses a glass side covered with gold nano discs that allows users to monitor changes in the transmission of light and determine the characteristics of nanoparticles as small as 25 nanometers in diameter. PANORAMA takes its name from Plasmonic Nano-aperture Label-free Imaging (PlAsmonic NanO-apeRture lAbel-free iMAging), signifying the key characteristics of the technology.
For this research, supported by the National Institutes of Health, it was a matter of counting the number of small EVs to detect cancer.
“Using a cutoff of 70 normalized small EV counts, all cancer samples from 205 patients were above this threshold except for one sample, and for healthy samples, from 106 healthy individuals, all but three were above this cutoff, giving a cancer detection sensitivity of 99.5% and specificity of 97.3%,” said Shih.
To further test the performance of the detection threshold of 70 normalized small EV counts in plasma, the team analyzed two independent sets of samples from stage I-IV or recurrent leiomyosarcoma/gastrointestinal stromal tumors and early-and-late-stage cholangiocarcinoma that were anonymously labeled and mixed in with healthy samples and achieved 100% accuracy.
“With further optimization, our approach may be a useful tool for cancer detection screening in particular and provide insights into the biology of cancer and small EVs,” said Shih.
His research team includes doctoral students Nareg Ohannesian and Mohammad Sadman Mallick, and collaborators Steven H. Lin, Simona F. Shaitelman, Chad Tang, Eileen H. Shinn, Wayne L. Hofstetter, Alexei Goltsov, Manal M. Hassan, Kelly K. Hunt, from M.D. Anderson Cancer Center. Shih and Lin founded Seek Diagnostics Inc. to commercialize this technology.

A new study from the UC Davis School of Medicine found striking differences at the cellular level between male and female mice with heart failure with preserved ejection fraction (HFpEF).
The findings could determine how HFpEF is treated in women compared to men.
With HFpEF, the heart muscle contracts normally but the heart is unable to fully relax and refill properly between beats. This condition is known as diastolic dysfunction. It can occur if the heart is too stiff or if the contraction process doesn’t shut off quickly enough between beats.
The study showed that the diastolic dysfunction in female mice resulted from altered heart filament proteins. In male mice, it resulted from the slow removal of calcium from heart cells between heartbeats, causing a slight contraction to remain between beats.
The findings were published in Cardiovascular Research.
“This study demonstrates the importance of conducting research on both male and female populations,” said Donald M. Bers, a senior author of the study. Bers is the chair of the Department of Pharmacology and the Joseph Silva Endowed Chair for Cardiovascular Research at the UC Davis School of Medicine. “If these same molecular male-female distinctions occur in obese diabetic patients with HFpEF, it may mean that the best therapeutic strategies for HFpEF in women may differ from those for men.”
Heart failure is when the heart cannot pump enough blood and oxygen to support the body. Approximately 6.2 million people in the U.S. have heart failure. The five-year mortality rate for heart failure is around 50%, although many factors can influence survival. About half of those with heart failure have HFpEF, and almost twice as many women have HFpEF compared to men. Men with the heart failure may be more at risk of cardiac arrhythmias and sudden cardiac death.

“Two hit” mouse model to study HFpEF
Obesity and diabetes are common in people with HFpEF. To study the disease, the researchers created a unique “two-hit” mouse model combining two factors.
For the first factor, the researchers used mice genetically lacking a leptin receptor. Leptin is a hormone that promotes satiety. Without it, appetite remains high and the animals become obese and diabetic. For the second factor, mice were exposed to an aldosterone infusion. Aldosterone is a hormone made by the adrenal gland. High levels of aldosterone cause fluid retention.
This animal model of heart failure and diabetes develops HFpEF, allowing researchers to analyze the cellular and molecular mechanisms of muscle contraction and relaxation in male and female mice.
The research team (left to right): Christopher Y. Ko, Juliana Mira Hernandez, Donald M. Bers, Erin Y. Shen and Bence Hegyi in in front of their key findings on the screen.
Dysregulation of calcium, titin
Calcium is critical in the activation of contraction and relaxation of heart muscle cells as well as the heart’s electrical activity. Calcium entering the heart cell at each beat causes the muscle to contract. It also helps drive the electric signal that synchronizes the contraction of the millions of heart muscle cells required for the heart to function as an efficient pump. Calcium is removed from the cell at each beat. This allows the heart to relax between beats and fill for the next beat.

In the male mice with HFpEF, the calcium removal from the heart muscle cells was slowed, preventing complete relaxation between beats. The male HFpEF mice also exhibited more abnormal heart rhythms, known as arrhythmias.
In contrast, the females with HFpEF exhibited normal calcium movements into and out of the heart cells. Instead, the researchers observed an increase in a shorter and stiffer form of titin (N2B). Titin is a protein in the heart that acts like a supportive spring. Researchers also observed phosphorylation (a molecular reaction) of titin and another heart filament protein, troponin I. Both the titin and troponin changes made the female heart cells functionally stiffer — making the heart harder to fill — even though calcium removal was normal.
“This study reveals different drug targets in males and females and will be a stepping-stone for future trials with sex-specific targeted drugs in HFpEF,” said Bence Hegyi, an associate project scientist in the Bers Lab and co-senior author of the study. “Potentially, women with this form of HFpEF could benefit from drugs that reduce cardiac stiffness. On the other hand, men with this form of HFpEF might benefit more from drugs that enhance calcium removal.”
Limitations
The researchers noted several limitations of the study. Although the mice in this study may be representative of the substantial number of HFpEF patients who have diabetes and are quite obese, many HFpEF patients may not be represented by this model. Multiple animal models will be needed to understand different subpopulations with HFpEF. Additional preclinical and clinical studies are needed to fully realize the potential benefits of this work.
Additional authors include Erin Shen, Christopher Ko, Emily Spencer, Daria Smoliarchuk and Julie Bossuyt from the UC Davis School of Medicine; Juliana Mira Hernandez from the UC Davis School of Medicine and the University of Antioquia, Medellin, Colombia; and Zaynab Hourani and Henk Granzier from the University of Arizona, Tucson.

The prevalence of post-traumatic stress disorder among college students rose to 7.5 percent in 2022, more than double the rate five years earlier, researchers found.Post-traumatic stress disorder diagnoses among college students more than doubled between 2017 and 2022, climbing most sharply as the coronavirus pandemic shut down campuses and upended young adults’ lives, according to new research published on Thursday.The prevalence of PTSD rose to 7.5 percent from 3.4 percent during that period, according to the findings. Researchers analyzed responses from more than 390,000 participants in the Healthy Minds Study, an annual web-based survey.“The magnitude of this rise is indeed shocking,” said Yusen Zhai, the paper’s lead author, who heads the community counseling clinic at the University of Alabama at Birmingham. His clinic had seen more young people struggling in the aftermath of traumatic events. So he expected an increase, but not such a large one.Dr. Zhai, an assistant professor in the Department of Human Studies, attributed the rise to “broader societal stressors” on college students, such as campus shootings, social unrest and the sudden loss of loved ones from the coronavirus.PTSD is a mental health disorder characterized by intrusive thoughts, flashbacks and heightened sensitivity to reminders of an event, continuing more than a month after it occurs.It is a relatively common disorder, with an estimated 5 percent of adults in the United States experiencing it in any given year, according to the most recent epidemiological survey conducted by the Department of Health and Human Services. Lifetime prevalence is 8 percent in women and 4 percent in men, the survey found.We are having trouble retrieving the article content.Please enable JavaScript in your browser settings.Thank you for your patience while we verify access. If you are in Reader mode please exit and log into your Times account, or subscribe for all of The Times.Thank you for your patience while we verify access.Already a subscriber? Log in.Want all of The Times? Subscribe.

7 minutes agoSharon Barbour

Researchers at Rice University have revealed a previously unknown function of opioid receptors in the development of the enteric nervous system (ENS), often referred to as the “brain in the gut.” This discovery challenges conventional understanding of opioid receptors, shedding new light on their significance beyond pain management and addiction.
Led by Rosa Uribe, an assistant professor of biosciences at Rice and a Cancer Prevention and Research Institute of Texas (CPRIT) Scholar, the research team identified the genes critical for ENS development by conducting a series of experiments using zebrafish embryos, which share many genetic similarities with humans. The ENS is a network of neurons in the gastrointestinal tract that plays a vital role in regulating digestive processes.
The team’s research was published in the PLOS ONE journal on May 29.
“We found that the opioid signaling pathway is required for the developmental formation of nerves in the gut, an understudied part of the body called the enteric nervous system,” Uribe said.
Using gene-editing techniques, the researchers selectively removed, or knocked out, a single gene from an entire population of zebrafish embryos to observe how these genetic alterations affected the formation of gut nerves. This process revealed novel genes, including those encoding opioid receptors, implicated in ENS development.
Contrary to previous assumptions, the researchers found that opioid receptors are not solely involved in pain perception and addiction but are also integral to the developmental formation of gut nerves.
“When these receptors were deactivated, the migration and maturation of enteric neurons along the gut were disrupted,” Uribe said. That disruption indicates the crucial role of opioid signaling pathways in ENS development.

The team’s findings open up new avenues for understanding digestive health and disease. Many infants born with missing gut nerves experience difficulties in passing stool, highlighting the potential impact of this research on pediatric medicine. Understanding the role of opioids in gut development may pave the way for innovative treatments for congenital digestive disorders.
“Our research unveils a new aspect of opioid receptor function and highlights their unexpected role in gut development,” Uribe said. “This could have profound implications for understanding digestive disorders and potentially lead to new therapeutic approaches.”
Moreover, the study identified other genes, such as VGF, with implications for gastrointestinal health. Further research in this area could uncover more insights into the complex interplay between genes, the nervous system and digestive function, said lead researcher and postdoctoral fellow Rodrigo Moreno Campos.
“Our finding is incredible and opens up a whole new avenue of enteric neurodevelopmental biology research in the field,” Moreno Campos said. “The implications for congenital, neurological and metabolic disease are great.”

Researchers from Cleveland Clinic and IBM recently published findings in the Journal of Chemical Theory and Computation that could lay the groundwork for applying quantum computing methods to protein structure prediction. This publication is the first peer-reviewed quantum computing paper from the Cleveland Clinic-IBM Discovery Accelerator partnership.
For decades, researchers have leveraged computational approaches to predict protein structures. A protein folds itself into a structure that determines how it functions and binds to other molecules in the body. These structures determine many aspects of human health and disease.
By accurately predicting the structure of a protein, researchers can better understand how diseases spread and thus how to develop effective therapies. Cleveland Clinic postdoctoral fellow Bryan Raubenolt, Ph.D., and IBM researcher Hakan Doga, Ph.D., spearheaded a team to discover how quantum computing can improve current methods.
In recent years, machine learning techniques have made significant progress in protein structure prediction. These methods are reliant on training data (a database of experimentally determined protein structures) to make predictions. This means that they are constrained by how many proteins they have been taught to recognize. This can lead to lower levels of accuracy when the programs/algorithms encounter a protein that is mutated or very different from those on which they were trained, which is common with genetic disorders.
The alternative method is to simulate the physics of protein folding. Simulations allow researchers to look at a given protein’s various possible shapes and find the most stable one. The most stable shape is critical for drug design.
The challenge is that these simulations are nearly impossible on a classical computer, beyond a certain protein size. In a way, increasing the size of the target protein is comparable to increasing the dimensions of a Rubik’s cube. For a small protein with 100 amino acids, a classical computer would need the time equal to the age of the universe to exhaustively search all the possible outcomes, says Dr. Raubenolt.
To help overcome these limitations, the research team applied a mix of quantum and classical computing methods. This framework could allow quantum algorithms to address the areas that are challenging for state-of-the-art classical computing, including protein size, intrinsic disorder, mutations and the physics involved in proteins folding. The framework was validated by accurately predicting the folding of a small fragment of a Zika virus protein on a quantum computer, compared to state-of-the-art classical methods.

The quantum-classical hybrid framework’s initial results outperformed both a classical physics-based method and AlphaFold2. Although the latter is designed to work best with larger proteins, it nonetheless demonstrates this framework’s ability to create accurate models without directly relying on substantial training data.
The researchers used a quantum algorithm to first model the lowest energy conformation for the fragment’s backbone, which is typically the most computationally demanding step of the calculation. Classical approaches were then used to convert the results obtained from the quantum computer, reconstruct the protein with its sidechains, and perform final refinement of the structure with classical molecular mechanics force fields. The project shows one of the ways that problems can be deconstructed into parts, with quantum computing methods addressing some parts and classical computing others, for increased accuracy.
“One of the most unique things about this project is the number of disciplines involved,” says Dr. Raubenolt. “Our team’s expertise ranges from computational biology and chemistry, structural biology, software and automation engineering, to experimental atomic and nuclear physics, mathematics, and of course quantum computing and algorithm design. It took the knowledge from each of these areas to create a computational framework that can mimic one of the most important processes for human life.”
The team’s combination of classical and quantum computing methods is an essential step for advancing our understanding of protein structures, and how they impact our ability to treat and prevent disease. The team plans to continue developing and optimizing quantum algorithms that can predict the structure of larger and more sophisticated proteins.
“This work is an important step forward in exploring where quantum computing capabilities could show strengths in protein structure prediction,” says Dr. Doga. “Our goal is to design quantum algorithms that can find how to predict protein structures as realistically as possible.”

While older drugs for epilepsy, taken while pregnant, have been shown in previous research to affect the creative thinking of children, a new study finds no effects on creativity for children born to those taking newer epilepsy drugs. This study is published in the May 29, 2024, online issue of Neurology®, the medical journal of the American Academy of Neurology.
Overall, the study found no effects on the children’s creative abilities or their executive function, which is a person’s ability to plan, focus, and manage multiple tasks. However, when researchers looked only at children with higher concentrations of these medications in the mother’s blood during the third trimester, the study found an association with poorer performance in tests of children’s executive function, but no effect on their creative abilities.
“Our findings highlight that even for epilepsy medications that are generally considered to be safe in pregnancy, dose adjustments should be made with a goal of reaching an optimal balance between controlling seizures and the minimizing negative effects on the developing child,” said study author Kimford Meador, MD, PhD, of Stanford University in Palo Alto, California and a Fellow of the American Academy of Neurology.
The study involved 251 children of female participants with epilepsy and 73 children of female participants without the disease.
Of those with epilepsy, most were taking just one epilepsy medication. Of this group, 81 people were on lamotrigine and 68 people were on levetiracetam.
The children were evaluated at age four and a half with a test of creative thinking where they were provided with a shape or figure and responded by completing or adding their own illustrations. This test assesses fluency, flexibility and originality abilities.
After adjusting for mothers’ IQ and education, researchers found no differences in the creativity scores between the children born to mothers with epilepsy and those born to mothers without the disease.

In addition, they found no differences in creativity between the children of mothers with epilepsy that could be linked to different levels of antiseizure medications found in mothers’ blood samples during the third trimester.
However, researchers found higher third trimester blood concentrations of these medications were associated with poorer performance on tests of executive skills. This link was mainly associated with exposure to levetiracetam.
“There is still so much to learn about the impact of a mother’s epilepsy medications on their child’s creative development,” said Meador. “More studies are needed, especially in older children, to assess the full effect of these medications on childhood development.”
A limitation of the study was that cognitive tests at age four and a half are not as accurate at predicting creativity and thinking skills in the teenage and adult years as tests taken at older ages.

When public health officials make policies about when and how vaccination programs are implemented, they must weigh the benefits and risks of how infectious diseases spread throughout the country. However, these analyses are often based on national-level data and, in some countries, may overlook nuances at the local level.
A new analysis by an international team, including Penn State researchers, revealed that the resulting recommendations may keep some countries from realizing the benefits of vaccination and globally eradicating diseases, such as rubella — a contagious viral infection that causes mild symptoms in children. The team examined data from Nigeria, one of 19 countries that hasn’t yet introduced rubella vaccination, as a case study. Their findings were published in the journal Vaccine.
“It’s this interesting challenge where rubella is a mild disease if you get it as a kid, but it’s high risk if you get it as an adult,” said senior author Matthew Ferrari, professor of biology and director of the Center for Infectious Disease Dynamics at the Huck Institutes of Life Sciences at Penn State. “All of the policy surrounding rubella vaccination has been guided by that risk in adults, which has been holding back the benefit of rubella vaccination in some countries.”
The primary concern among adults is the potential risk for congenital rubella syndrome (CRS), a serious health condition that can occur if a pregnant person contracts the virus. When an infectious disease like rubella is common, people are more likely to contract it earlier in life. And because the rubella virus is immunizing, those who are infected as children won’t have pregnancies at risk of CRS when they are older.
Vaccination, on the other hand, reduces the amount of circulating virus, meaning individuals who were not vaccinated as children are less likely to be infected with rubella by adolescence or adulthood, Ferrari explained. As a result, even as the total number of rubella cases goes down with vaccination, the number of rubella infections in people of reproductive age — who were neither infected nor vaccinated as children — increases, putting those pregnancies at risk of CRS. Because of this complex dynamic, the World Health Organization (WHO) recommends that countries demonstrate that they can achieve a coverage level of 80% or greater, through either routine immunization or supplemental campaigns, before introducing rubella vaccination. The conventional wisdom has been that when vaccination coverage is above this threshold, the reduced risk of CRS due to less rubella virus offsets the paradoxical increase in CRS risk because infections tend to happen later in life, Ferrari explained.
The research team, working in partnership with the U.S. Centers of Disease Control and Prevention and the Nigeria Centre for Disease Control and Prevention, studied the epidemiology of rubella in Nigeria. Rubella is a comparatively rare disease, so it’s difficult to quantify the potential harm and risk of CRS. These assessments are further complicated by the fact that Nigeria, Ferrari said, is a country with disparate ranges of wealth, vaccination coverage, health care access and birth rates, all of which play a role in infection and CRS risk.
To gain a better understanding of the factors at play, the team analyzed data from a nationally representative serosurvey, which detects the presence of antibodies in blood. The data allowed the researchers to see how many people, particularly women of reproductive age, had rubella antibodies, how many were potentially at risk of rubella infection and where the infection risk was greatest geographically. They identified regional differences in transmission between the northern versus southern part of the country, finding that transmission in the north was two-times higher compared to the south. They were also able to estimate the number of pregnancies affected by rubella infection today.
“We grounded the current infection risk and potential pregnancies at risk in strong empirical data and real-world phenomena,” Ferrari said. “Parts of the country can already vaccinate more than 80% of kids, based on their current rate of measles vaccination, but low vaccination coverage in the north is a barrier to introduction across the whole country under the current recommendation.”
What’s more, the concern about increased CRS cases may not be as bad as conventionally believed, Ferrari noted. The team’s new estimates of transmission rates show that the 80% threshold is conservative and that introducing a rubella vaccination program in Nigeria today could reduce the number of CRS cases by thousands in the first five years. “Some states could see CRS risk increase by hundreds of cases,” he said, “but that increased risk would not come to fruition until 10 years down the road” — providing a decade for public health officials to implement policies and programs to prevent this possibility.
“Strengthening and improving routine immunization programs and advancing them everywhere in the world is a benefit to everyone in the world. The more we do this, the elimination of rubella as a virus on this planet is entirely feasible,” Ferrari said.

Skin grafting is an essential procedure used to treat severe skin wounds. In the case of extensive wounds, however, it can be challenging to harvest enough donor skin, and generating artificial skin substitutes that include hair follicles and sweat glands and can engraft on deep wounds has not been successful. Now, researchers from Japan report a new way to “grow your own” donor skin that could help improve the success of skin graft generation.
In a study published last month in Nature Communications, researchers from Tokyo Medical and Dental University (TMDU) have revealed that growing donor skin in another species yields surprisingly robust and functional skin grafts.
The gold standard for treating burn wounds is autologous skin grafting, a process in which sheets of skin containing both the epidermis (the outer layer) and the dermis (the deeper layer) are transferred from other parts of the patient’s body to cover the wounded area. However, for large wounds it can be difficult to harvest enough skin from the limited donor sites. Split-thickness grafts that contain mostly epidermis with only some of dermis can be used to cover larger areas, but they do not include features like hair and sweat glands, and are more prone to shrinkage and scarring.
“As alternatives to autologous skin grafts, artificial skin substitutes including cultured epidermis and reconstituted skins have been developed,” says the lead author of the study Dr. Hisato Nagano. “These options are inferior, though, as cultured epidermis can only be used for shallow wounds, and the engraftment rate of reconstituted skins is low.”
To provide proof-of-concept for a new way to produce autologous skin grafts, the researchers generated skin grafts by introducing a mutation into mouse fetuses that made them unable to grow mature epidermis. These fetuses were then injected with mouse stem cells and allowed to develop normally until birth, when their skin growth was analyzed.
“The results were very surprising,” explains Dr. Naoaki Mizuno, the corresponding author. “Not only were the chimeric mice born covered with large patches of skin derived from the injected cells, but these patches also survived up to 3 months when grafted onto mature mice, and even grew fur.”
Intriguingly, injecting the same mutated mouse embryos with human skin cells yielded similar results: as the mice developed in utero, they grew sheets of human skin that mimicked the structure and organization of mature epidermis.
“Our findings suggest that semi-autologous skin grafts containing hair follicles and other skin appendages can be generated in vivo and engrafted successfully,” says Dr. Hiromitsu Nakauchi, senior author.
Given that mouse embryos can only grow small amounts of skin, the next step would be to scale up the process to larger animals with a longer gestation period to generate large human skin grafts. This approach, which involves generating only skin tissue, could help avoid ethical concerns about using human-animal chimeras to produce organs for medical use.

Researchers at Baylor College of Medicine and collaborating institutions have discovered that a protein called hnRNPM helps protect the integrity of the process cells use to make proteins. hnRNPM works by preventing the cell from making mistakes while it is putting together the different components leading to newly produced proteins. In cancer cells, loss of hnRNPM triggers an interferon immune response, suggesting that this protein may hold clinical promise. The findings appeared in Molecular Cell.
“Synthesizing a protein is like putting together the different parts of a machine. If during the assembly process parts that do not belong are incorporated into the machine, the final product would not fulfill its intended function, disturbing the normal workings of the cell and potentially leading to disease,” said co-corresponding author Dr. Chonghui Cheng, professor of the Lester and Sue Smith Breast Center, molecular and human genetics and molecular and cellular biology at Baylor. “Despite the many opportunities for such mistakes, cells make proteins highly accurately and precisely. Here we investigated what helps cells maintain the integrity of this vital process.”
When a cell needs to synthesize a protein, it begins by getting the instructions from the corresponding gene in the DNA. Imagine a necklace with beads separated by empty pieces of the string that threads them together as an analogy for the DNA molecule carrying the instructions to make a protein. The beads represent the exons, the segments of a DNA molecule containing the information coding for the protein of interest. The string between beads represents introns, DNA segments separating the exons. Introns do not code for the protein itself, they help guide the process that regulates gene expression.
To make a functional protein, the cell first transcribes the DNA information contained in exons and introns into a pre-mRNA molecule. Continuing with the analogy, the cell makes a pre-mRNA necklace with beads (exons) interspaced with string (introns). Next, from the pre-mRNA necklace the cell makes an mRNA necklace by splicing together the beads leaving out the string (introns) in between. This mRNA is finally translated into a functional protein.
The researchers investigated how cells prevented errors that could occur during the step in which exons are spliced together, which could lead to abnormal mRNA molecules. They looked into splice sites, the segments that mark the location for the splicing of exons.
Pseudo splice sites and cryptic splicing
“The human genome has introns that are significantly longer than exons. These long introns contain numerous small segments, called pseudo splice sites, that are highly similar to the known correct splice sites,” said Cheng, a member of Baylor’s Dan L Duncan Comprehensive Cancer Center. “If pseudo splice sites are used instead of the correct splice sites during protein synthesis, the resulting mRNA will contain the wrong instructions — cryptic splicing — that could alter normal cell function.”
The researchers discovered that despite the presence of many pseudo splice sites, RNA splicing occurs accurately and precisely thanks to the RNA-binding protein hnRNPM. They discovered this by developing a bioinformatic pipeline that nominates cryptic sequences from datasets of RNA sequences.

“We found that hnRNPM preferentially binds to introns at regions containing pseudo splice sites,” said first author Dr. Rong Zheng, a graduate student in the Cheng lab while she was working on this project. “Their binding prevents or blocks the use of these splice sites when synthesizing RNA molecules, preventing cryptic splicing and therefore maintaining the integrity of the process.”
The team also discovered that in the absence of hnRNPM, cryptic splicing can form double stranded RNA (dsRNA), which is known to trigger interferon immune responses. “Tumors with low hnRNPM show increased cryptic splicing, interferon immune responses and immune infiltration,” Cheng said. “This finding suggests that inhibiting hnRNPM or enhancing the splicing of dsRNA-forming cryptic exons could represent innovative methods to activate immunity in patients with cancer.”
Other contributors to this work include Mikayla Dunlap, Georg O.M. Bobkov, Carlos Gonzalez-Figueroa, Khushali J. Patel, Jingyi Lyu, Samuel E. Harvey, Tracey W. Chan, Giovanni Quinones-Valdez, Mudra Choudhury, Charlotte A. Le Roux, Mason D. Bartels, Amy Vuong, Ryan A. Flynn, Howard Y. Chang, Eric L Van Nostrand and co-corresponding author Xinshu Xiao. The authors are affiliated with one of the following institutions: Baylor College of Medicine, University of California — Los Angeles, Stanford University School of Medicine.
This research was supported in part by grants from NIH (R35-CA209919, R01CA262686, R01AG078950 and R35GM131876) and cancer research scholarships from the Cancer Prevention Research Institute of Texas Scholars (RR200040 and RR160009).