Type 1 diabetes (also known as autoimmune diabetes) is a devastating and life-long disease, in which the patient’s immune cells wrongly destroy the insulin producing beta cells in the pancreas. People living with autoimmune diabetes need to test their blood sugar and inject insulin throughout their lives to control their blood sugars and prevent complications.

Autoimmune diabetes with clinical onset in very early childhood is rare and can result from a variety of genetic variants. However, there are many cases of early onset diabetes without known genetic explanation. In addition, some cancer patients treated with a category of immunotherapy known as immune checkpoint inhibitors — which target the same pathway that the mutation was found in — are prone to developing autoimmune diabetes. The reason why only this category of cancer immunotherapy can trigger autoimmune diabetes is not well understood. Like type 1 diabetes, genetic or immunotherapy-associated autoimmune diabetes requires life-long insulin replacement therapy — there is currently no cure.

The new research, published in the Journal of Experimental Medicine, began when researchers studied two siblings who were diagnosed with a rare genetic form of autoimmune diabetes in the first weeks of life. The University of Exeter offers free genetic testing worldwide for babies diagnosed with diabetes before they are nine months old. For most of these babies, this service provides a genetic diagnosis and in around half of these babies, it allows for a change in treatment.

When researchers tested the two siblings in the study, no mutation in any of the known causes was identified. The Exeter team then performed whole genome sequencing to look for previously unknown causes of autoimmune diabetes. Through this sequencing, they found a mutation in the gene encoding PD-L1 in the siblings and realised it could be responsible for their very-early-onset autoimmune diabetes.

Study authorDr Matthew Johnson, from the University of Exeter, UK, said: “PD-L1 has been particularly well studied in animal models because of its crucial function in sending a stop signal to the immune system and its relevance to cancer immunotherapy. But, to our knowledge, nobody has ever found humans with a disease-causing mutation in the gene encoding PD-L1. We searched the globe, looking at all the large-scale datasets that we know of, and we haven’t been able to find another family. These siblings therefore provide us with a unique and incredibly important opportunity to investigate what happens when this gene is disabled in humans.”

The PD-L1 protein is expressed on many different cell types. Its receptor, PD-1, is expressed exclusively on immune cells. When the two proteins bind together it provides a stop signal to the immune system, preventing collateral damage to the bodies tissues and organs.

Researchers from the Rockefeller Institute in New York and King’s College London joined forces with Exeter to study the siblings, with funding from Wellcome, The Leona M. and Harry B. Helmsley Charitable Trust, Diabetes UK, and the US National Institutes for Health. After contacting the family’s clinician in Morocco, the Exeter team visited the siblings where they were living to collect samples and return them to King’s College London, within the crucial ten-hour window for analysis while the immune cells were still alive. The London and New York teams then performed extensive analysis on the siblings’ cells.

Study co-author Dr Masato Ogishi, from the Rockefeller University in New York, said: “We first showed that the mutation completely disabled the function of PD-L1 protein. We then studied the immune system of the siblings to look for immunological abnormalities that could account for their extremely early-onset diabetes. As we previously described another two siblings with PD-1 deficiency, both of whom had multi-organ autoimmunity including autoimmune diabetes and extensive dysregulation in their immune cells, we expected to find severe dysregulation of the immune system in the PD-L1-deficient siblings. To our great surprise, their immune systems looked pretty much normal in almost all aspects throughout the study. Therefore, PD-L1 is certainly indispensable for preventing autoimmune diabetes but is dispensable for many other aspects of human immune system. We think that PD-L2, another ligand of PD-1, albeit less well-studied than PD-L1, may be serving as a back-up system when PD-L1 is not available. This concept needs to be further investigated in the context of artificial blockade for PD-L1 as cancer immunotherapy.”

Study co-author Professor Timothy Tree, from King’s College London, said: “Through studying this one set of siblings — unique in the world to our knowledge — we have found that the PD-L1 gene is essential for avoiding autoimmune diabetes, but is not essential for ‘everyday’ immune function. This leads us to the grand question; ‘what is the role of PD-L1 in our pancreas making it critical for preventing our immune cells destroying our beta cells?’ We know that under certain conditions beta cells express PD-L1. However, certain types of immune cells in the pancreas also express PD-L1. We now need to work out the “communication” between different cell types that is critical for preventing autoimmune diabetes.

“This finding increases our knowledge of how autoimmune forms of diabetes such as type 1 diabetes develop. It opens up a new potential target for treatments that could prevent diabetes in the future. Simultaneously, it gives new knowledge to the cancer immunotherapy field by uniquely providing the results of completely disabling PD-L1 in a person, something you could never manipulate in studies. Reducing PD-L1 is already effective for cancer treatment, and boosting it is now being investigated as a type 1 diabetes treatment — our findings will help accelerate the search for new and better drugs.”

Dr Lucy Chambers, Head of Research Communications at Diabetes UK, said: “Pioneering treatments that alter the behaviour of the immune system to hold off its attack on the pancreas are already advancing type 1 diabetes treatment in the USA, and are awaiting approval here in the UK.

“By zeroing in on the precise role of an important player in the type 1 diabetes immune attack, this exciting discovery could pave the way for treatments that are more effective, more targeted and more transformational for people with or at risk of type 1 diabetes.”

Helmsley Program Officer Ben Williams said: “New drugs often fail in development because scientific discoveries made in animal models don’t translate into humans. As such, drug developers strongly prefer to pursue new drugs where human genetic evidence supports the drug’s target. This study provides such compelling evidence that PD-L1 is a high-priority target to treat T1D, and should be pursued with the ambition of eventually reducing the burden of this difficult to manage disease.”

The paper is entitled ‘Human inherited PD-L1 deficiency is clinically and immunologically less severe than PD-1 deficiency’ and is published in the Journal of Experimental Medicine. The research was supported by the National Institute of Health and Care Research (NIHR) Exeter Biomedical Research Centre and The NIHR Exeter Clinical Research Facility.

The test, called MyProstateScore2.0, or MPS2, looks at 18 different genes linked to high-grade prostate cancer. In multiple tests using urine and tissue samples from men with prostate cancer, it successfully identified cancers classified as Gleason 3+4=7 or Grade Group 2 (GG2), or higher. These cancers are more likely to grow and spread compared to Gleason 6 or Grade Group 1 prostate cancers, which are unlikely to spread or cause other impact. More than one-third of prostate cancer diagnoses are this low-grade form. Gleason and Grade Group are both used to classify how aggressive prostate cancer is.

Results are published in JAMA Oncology.

“Our standard test is lacking in terms of its ability to clearly pick out those who have significant cancer. Twenty years ago, we were looking for any kind of cancer. Now we realize that slow-growing cancer doesn’t need to be treated. All of a sudden, the game changed. We went from having to find any cancer to finding only significant cancer,” said co-senior study author John T. Wei, M.D., David A. Bloom Professor of Urology at Michigan Medicine.

Prostate-specific antigen, or PSA, remains the linchpin of prostate cancer detection. MPS2 improves upon a urine-based test developed by the same U-M team nearly a decade ago, following a landmark discovery of two genes that fuse to cause prostate cancer. The original MPS test, which is used today, looked at PSA, the gene fusion TMPRSS2::ERG, and another marker called PCA3.

“There was still an unmet need with the MyProstateScore test and other commercial tests currently available. They were detecting prostate cancer, but in general they were not doing as good a job in detecting high-grade or clinically significant prostate cancer. The impetus for this new test is to address this unmet need,” said co-senior author Arul M. Chinnaiyan, M.D., Ph.D., director of the Michigan Center for Translational Pathology. Chinnaiyan’s lab discovered the T2::ERG gene fusion and developed the initial MPS test.

To make MyProstateScore even stronger at identifying high-grade cancers, researchers used RNA sequencing of more than 58,000 genes and narrowed it to 54 candidates uniquely overexpressed specifically in higher-grade cancers. They tested the biomarkers against urine samples collected and stored at U-M through another major study, the National Cancer Institute’s Early Detection Research Network. This included about 700 patients from 2008-2020 who came for a prostate biopsy due to an elevated PSA level.

This first step narrowed the field to 18 markers that consistently correlated with higher grade disease. The test still includes the original MPS markers, plus 16 additional biomarkers to complement them.

From there, the team reached out to the larger Early Detection Research Network (EDRN), a consortium of more than 30 labs across the country that are similarly collecting samples. This ensured a diverse, national sampling. Knowing no specific details about the samples, the U-M team performed MPS2 testing on more than 800 urine samples and sent results back to collaborators at the NCI-EDRN. The NCI-EDRN team assessed MPS2 results against the patient records.

MPS2 was shown to be better at identifying GG2 or higher cancers. More importantly, it was nearly 100% correct at ruling out GG1 cancer.

“If you’re negative on this test, it’s almost certain that you don’t have aggressive prostate cancer,” said Chinnaiyan, S. P. Hicks Endowed Professor of Pathology and professor of urology at Michigan Medicine.

Moreover, MPS2 was more effective at helping patients avoid unnecessary biopsies. While 11% of unnecessary biopsies were avoided with PSA testing alone, MPS2 testing would avoid up to 41% of unnecessary biopsies.

“Four of 10 men who would have a negative biopsy will have a low risk MPS2 result and can confidently skip a biopsy. If a man has had a biopsy before, the test works even better,” Wei explained.

For example, a patient may get a prostate biopsy due to an elevated PSA, but no cancer is detected. The patient is followed over time and if his PSA inches up, he would typically need another biopsy.

“In those men who have had a biopsy before and are being considered for another biopsy, MPS2 will identify half of those whose repeat biopsy would be negative. Those are practical applications for patients out there. Nobody wants to say sign me up for another biopsy. We are always looking for alternatives and this is it,” Wei said.

MPS2 is currently available through LynxDx, which is University of Michigan spin-off company that has an exclusive license from the university to commercialize MPS2. Patients interested in learning more can call the Michigan Medicine Cancer AnswerLine at 800-865-1125.

The paper’s first authors are Jeffrey J. Tosoian, M.D., M.P.H., who is now at Vanderbilt University, and Yuping Zhang, Ph.D., and Lanbo Xiao, Ph.D., at U-M. Additional authors are Cassie Xie; Nathan L. Samora, M.D.; Yashar S. Niknafs, Ph.D.; Zoey Chopra; Javed Siddiqui; Heng Zheng, M.D.; Grace Herron; Neil Vaishampayan; Hunter S. Robinson, M.D.; Kumaran Arivoli; Bruce J. Trock, Ph.D.; Ashley E. Ross, M.D., Ph.D.; Todd M. Morgan, M.D.; Ganesh S. Palapattu, M.D.; Simpa S. Salami, M.D., M.P.H.; Lakshmi P. Kunju, M.D.; Scott A. Tomlins, M.D., Ph.D.; Lori J. Sokoll, Ph.D.; Daniel W. Chan, Ph.D.; Sudhir Srivastava, Ph.D.; Ziding Feng, Ph.D.; Martin G. Sanda, M.D.; Yingye Zheng, Ph.D.

Funding for this work is from the Michigan-Vanderbilt Early Detection Research Network Biomarker Characterization Center and Data Management and Coordinating Center, which are through the National Cancer Institute grants U2C CA271854 and U24 CA086368. Additional funding is from NCI grants P50 CA186786, R35 CA231996, U24 CA115102, U01 CA113913; Prostate Cancer Foundation; Howard Hughes Medical Institute; and the American Cancer Society.

Disclosures: Chinnaiyan serves on the advisory boards of Tempus, LynxDx, Ascentage Pharmaceuticals, Medsyn therapeutics, Esanik and RAAPTA therapeutics. Tomlins is an equity holder and chief medical officer of Strata Oncology. LynxDx has obtained an exclusive license from the University of Michigan to commercialize MPS2 and the TMPRSS2-ERG gene fusion. Tosoian and Chinnaiyan are equity holders and scientific advisers to LynxDx. Siddiqui, Zhang, Xiao and Niknafs have served as scientific advisers to LynxDx.

Current approaches to autism research involve observing and understanding the disorder through the study of its behavioral consequences, using techniques like functional magnetic resonance imaging that map the brain’s responses to input and activity, but little work has been done to understand what’s causing those responses.

However, researchers with UVA’s College and Graduate School of Arts & Sciences have been able to better understand the physiological differences between the brain structures of autistic and non-autistic individuals through the use of Diffusion MRI, a technique that measures molecular diffusion in biological tissue, to observe how water moves throughout the brain and interacts with cellular membranes. The approach has helped the UVA team develop mathematical models of brain microstructures that have helped identify structural differences in the brains of those with autism and those without.

“It hasn’t been well understood what those differences might be,” said Benjamin Newman, a postdoctoral researcher with UVA’s Department of Psychology, recent graduate of UVA School of Medicine’s neuroscience graduate program and lead author of a paper published this month in PLOS: One. “This new approach looks at the neuronal differences contributing to the etiology of autism spectrum disorder.”

Building on the work of Alan Hodgkin and Andrew Huxley, who won the 1963 Nobel Prize in Medicine for describing the electrochemical conductivity characteristics of neurons, Newman and his co-authors applied those concepts to understand how that conductivity differs in those with autism and those without, using the latest neuroimaging data and computational methodologies. The result is a first-of-its-kind approach to calculating the conductivity of neural axons and their capacity to carry information through the brain. The study also offers evidence that those microstructural differences are directly related to participants’ scores on the Social Communication Questionnaire, a common clinical tool for diagnosing autism.

“What we’re seeing is that there’s a difference in the diameter of the microstructural components in the brains of autistic people that can cause them to conduct electricity slower,” Newman said. “It’s the structure that constrains how the function of the brain works.”

One of Newman’s co-authors, John Darrell Van Horn, a professor of psychology and data science at UVA, said, that so often we try to understand autism through a collection of behavioral patterns which might be unusual or seem different.

“But understanding those behaviors can be a bit subjective, depending on who’s doing the observing,” Van Horn said. “We need greater fidelity in terms of the physiological metrics that we have so that we can better understand where those behaviors coming from. This is the first time this kind of metric has been applied in a clinical population, and it sheds some interesting light on the origins of ASD.”

Van Horn said there’s been a lot of work done with functional magnetic resonance imaging, looking at blood oxygen related signal changes in autistic individuals, but this research, he said “Goes a little bit deeper.”

“It’s asking not if there’s a particular cognitive functional activation difference; it’s asking how the brain actually conducts information around itself through these dynamic networks,” Van Horn said. “And I think that we’ve been successful showing that there’s something that’s uniquely different about autistic-spectrum-disorder-diagnosed individuals relative to otherwise typically developing control subjects.”

Newman and Van Horn, along with co-authors Jason Druzgal and Kevin Pelphrey from the UVA School of Medicine, are affiliated with the National Institute of Health’s Autism Center of Excellence (ACE), an initiative that supports large-scale multidisciplinary and multi-institutional studies on ASD with the aim of determining the disorder’s causes and potential treatments.

According to Pelphrey, a neuroscientist and expert on brain development and the study’s principal investigator, the overarching aim of the ACE project is to lead the way in developing a precision medicine approach to autism.

“This study provides the foundation for a biological target to measure treatment response and allows us to identify avenues for future treatments to be developed,” he said.

Van Horn added that study may also have implications for the examination, diagnosis, and treatment of other neurological disorders like Parkinson’s and Alzheimer’s.

“This is a new tool for measuring the properties of neurons which we are particularly excited about. We are still exploring what we might be able to detect with it,” Van Horn said.

Perez’s research team included two graduate students from UF, Arup Mondal and Bhumika Singh, and a handful of researchers from Rutgers University and Rensselaer Polytechnic Institute. The team published their findings in Angewandte Chemie, a leading chemistry journal based in Germany.

Named the AF-CBA Pipeline, this innovative tool offers unparalleled accuracy and speed in pinpointing the strongest peptide binders to a specific protein. It does this by using AI to simulate molecular interactions, sorting through thousands of candidate molecules to identify the molecule that interacts best with the protein of interest.

The AI-driven approach allows the pipeline to perform these actions in a fraction of the time it would take humans or traditional physics based-approaches to accomplish the same task.

“Think of it like a grocery store,” Perez explained. “When you want to buy the best possible fruit, you have to compare sizes and aspects. There are too many fruits to try them all of course, so you compare a few before making a selection. This AI method, however, can not only try them all, but can also reliably pick out the best one.”

Typically, the proteins of interest are the ones that cause the most damage to our bodies when they misbehave. By finding what molecules interact with these problematic proteins, the pipeline opens avenues for targeted therapies to combat ailments such as inflammation, immune dysregulation, and cancer.

“Knowing the structure of the strongest peptide binder in turn helps us in the rational designing of new drug therapeutics,” Perez said.

The groundbreaking nature of the pipeline is enhanced by its foundation on pre-existing technology: a program called AlphaFold. Developed by Google Deepmind, AlphaFold uses deep learning to predict protein structures. This reliance on familiar technology will be a boon for the pipeline’s accessibility to researchers and will help ensure its future adoption.

Moving forward, Perez and his team aim to expand their pipeline to gain further biological insights and inhibit disease agents. They have two viruses in their sights: murine leukemia virus and Kaposi’s sarcoma virus. Both viruses can cause serious health issues, especially tumors, and interact with as-of-now unknown proteins.

“We want to design novel libraries of peptides,” Perez said. “AF-CBA will allow us to identify those designed peptides that bind stronger than the viral peptides.”

In a new study, scientists at the Salk Institute help explain how CBN protects the brain against aging and neurodegeneration, then use their findings to develop potential therapeutics. The researchers created four CBN-inspired compounds that were more neuroprotective than the standard CBN molecule — one of which was highly effective in treating traumatic brain injury in a Drosophila fruit fly model.

The findings, published in Redox Biologyon March 29, 2024, suggest promise for CBN in treating neurological disorders like traumatic brain injury, Alzheimer’s disease, and Parkinson’s disease, and also highlight how further studies of CBN’s effects on the brain could inspire the development of new therapies for clinical use.

“Not only does CBN have neuroprotective properties, but its derivatives have the potential to become novel therapeutics for various neurological disorders,” says Research Professor Pamela Maher, senior author of the study. “We were able to pinpoint the active groups in CBN that are doing that neuroprotection, then improve them to create derivative compounds that have greater neuroprotective ability and drug-like efficacy.”

Many neurological disorders involve the death of brain cells called neurons, due to the dysfunction of their power-generating mitochondria. CBN achieves its neuroprotective effect by preventing this mitochondrial dysfunction — but how exactly CBN does this, and whether scientists can improve CBN’s neuroprotective abilities, has remained unclear.

The Salk team previously found that CBN was modulating multiple features of mitochondrial function to protect neurons against a form of cell death called oxytosis/ferroptosis. After uncovering this mechanism of CBN’s neuroprotective activity, they began applying both academic and industrial drug discovery methods to further characterize and attempt to improve that activity.

First, they broke CBN into small fragments and observed which of those fragments were the most effective neuroprotectors by chemically analyzing the fragment’s properties. Second, they designed and constructed four novel CBN analogs — chemical look-alikes — in which those fragments were amplified, then moved them on to drug screening.

“We were looking for CBN analogs that could get into the brain more efficiently, act more quickly, and produce a stronger neuroprotective effect than CBN itself,” says Zhibin Liang, first author and postdoctoral researcher in Maher’s lab. “The four CBN analogs we landed on had improved medicinal chemical properties, which was exciting and really important to our goal of using them as therapeutics.”

To test the chemical medicinal properties of the four CBN analogs, the team applied them to mouse and human nerve cell cultures. When they initiated oxytosis/ferroptosis in three different ways, they found that each of the four analogs 1) were able to protect the cells from dying, and 2) had similar neuroprotective abilities compared to regular CBN.

The successful analogs were then put to the test in a Drosophila fruit fly model of traumatic brain injury. One of the analogs, CP1, was especially effective in treating traumatic brain injury — producing the highest survival rate after condition onset.

“Our findings help demonstrate the therapeutic potential of CBN, as well as the scientific opportunity we have to replicate and refine its drug-like properties,” says Maher. “Could we one day give this CBN analog to football players the day before a big game, or to car accident survivors as they arrive in the hospital? We’re excited to see how effective these compounds might be in protecting the brain from further damage.”

In the future, the researchers will continue to screen and characterize these CBN analogs and refine their chemical designs. They will also begin looking more closely at age-related neurodegeneration and changes in brain cells, particularly in mitochondria, asking how we can better suit these drug-like compounds to promote cellular health and prevent neuronal dysfunction with age.

Other authors include David Soriano-Castell and Wolfgang Fischer of Salk; and Alec Candib and Kim Finley of the Shiley Bioscience Center at San Diego State University.

The work was supported by the Paul F. Glenn Center for Biology of Aging Research at the Salk Institute, the Bundy Foundation, the Shiley Foundation, the National Institutes of Health (R01AG067331, R21AG064287, R01AG069206, RF1AG061296, R21AG067334, NCI CCSG P30CA01495, NlA P30AG068635, S10OD021815), and the Helmsley Center for Genomic Medicine.

Despite the challenges posed by limited preservation of archaeological assemblages and organic remains in arid environments, these discoveries are reshaping our understanding of the region’s rich cultural heritage.

One such breakthrough led by Griffith University’s Australian Research Centre for Human Evolution (ARCHE), in collaboration with international partners, comes from the exploration of underground settings, including caves and lava tubes, which have remained largely untapped reservoirs of archaeological abundance in Arabia.

Through meticulous excavation and analysis, researchers have uncovered a wealth of evidence at Umm Jirsan, spanning from the Neolithic to the Chalcolithic/Bronze Age periods (~10,000-3,500 years ago).

“Our findings at Umm Jirsan provide a rare glimpse into the lives of ancient peoples in Arabia, revealing repeated phases of human occupation and shedding light on the pastoralist activities that once thrived in this landscape,” said Dr Mathew Stewart, the lead researcher and a Research Fellow at ARCHE.

“This site likely served as a crucial waypoint along pastoral routes, linking key oases and facilitating cultural exchange and trade.”

Rock art and faunal records attest to the pastoralist use of the lava tube and surrounding areas, painting a vivid picture of ancient lifeways.

Depictions of cattle, sheep, goat and dogs corroborate the prehistoric livestock practices and herd composition of the region.

Isotopic analysis of animal remains indicates that livestock primarily grazed on wild grasses and shrubs, while humans maintained a diet rich in protein, with a notable increase in the consumption of C3 plants over time, suggesting the emergence of oasis agriculture.

“While underground localities are globally significant in archaeology and Quaternary science, our research represents the first comprehensive study of its kind in Saudi Arabia,” added Professor Michael Petraglia, Director of ARCHE.

“These findings underscore the immense potential for interdisciplinary investigations in caves and lava tubes, offering a unique window into Arabia’s ancient past.”

The research at Umm Jirsan underscores the importance of collaborative, multidisciplinary approaches to archaeological inquiry and highlights the significance of Arabia’s archaeological heritage on the global stage.

Researchers involved in this study work in close partnership with the Heritage Commission, Saudi Ministry of Culture, and the Saudi Geological Survey. Additional partners include King Saud University and key institutions in the UK, the USA, and Germany.