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Siblings with unique genetic change help scientists progress drug search for type 1 diabetes – Science Daily

Two siblings who have the only known mutations in a key gene anywhere in the world have helped scientists gain new insights that could help progress the search for new treatments in type 1 diabetes.

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.

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Enteric parasites Cyclospora cayetanensis and Cryptosporidium hominis in domestic and wildlife animals in Ghana – Parasites & Vectors – Parasites & Vectors

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    NASA solar sail boom demonstrator reaches orbit – The Register

    NASA’s Advanced Composite Solar Sail System (ACS3) mission has made contact with Earth and confirmed that all is well with the diminutive spacecraft.

    Engineers established two-way communication with the spacecraft a few days after launch as the microwave oven-sized CubeSat passed over the ground hub located at Santa Clara University’s Robotics Systems Lab in Santa Clara, California.

    Having confirmed the spacecraft was healthy, engineers can work on the mission’s commissioning phase, which is expected to last between one and two months. Once done, the spacecraft can then deploy the four booms that span the diagonals of the square and unroll the solar sail.

    Once that’s done, the spacecraft will conduct a series of tests to demonstrate that it can change its orbit by angling the sail. A successful demonstration will lay the way for larger sails; the sail of ACS3 has an area of 80 square meters – large enough to appear as a bright star in the sky but not enough for missions to the Moon, Mars, and beyond.

    According to NASA, “This boom design could potentially support future solar sails as large as 5,400 square feet (500 square meters), about the size of a basketball court, and technology resulting from the mission’s success could support sails of up to 21,500 square feet (2,000 square meters) – about half a soccer field.”

    But first, it has to work. Cameras mounted on the spacecraft will capture the deployment of the sail, its shape, and its symmetry.

    ACS3 was launched on April 23, 2024, on a Rocket Lab Electron and deposited in a highly circular orbit at 1,000 km.

    The primary payload on the launch was NEONSAT-1, an Earth observation satellite and the first of a constellation of 11 spacecraft for the Korea Advanced Institute of Science and Technology (KAIST). NEONSAT-1 was deployed to a 520 km orbit before the Electron Kick Stage completed multiple in-space burns of its Curie engine.

    A final burn, following the deployment of ACS3, was performed to speed up the kick stage’s eventual de-orbit. ®

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    Archaeologists unveil face of Neanderthal woman 75,000 years after she died: “High stakes 3D jigsaw puzzle” – CBS News

    A British team of archaeologists on Thursday revealed the reconstructed face of a 75,000-year-old Neanderthal woman, as researchers reappraise the perception of the species as brutish and unsophisticated. 

    Named Shanidar Z after the cave in Iraqi Kurdistan where her skull was found in 2018, the latest discovery has led experts to probe the mystery of the forty-something Neanderthal woman laid to rest in a sleeping position beneath a huge vertical stone marker.

    The lower part of her skeleton is believed to have been excavated in 1960 during groundbreaking excavations by American archaeologist Ralph Solecki in which he found the remains of at least 10 Neanderthals.

    “I think she can help us connect with who they were,” said Dr. Emma Pomeroy, a palaeo-anthropologist on the project from the University of Cambridge.

    BRITAIN-IRIAQ-ARCHAEOLOGY-NEANDERTHAL
    Associate Professor in the Evolution of Health, Diet and Disease, Dr Emma Pomeroy, poses for a photograph with the rebuilt skull and a physical reconstruction of the face and head, of a 75,000-year-old Neanderthal woman, named Shanidar Z, at the University of Cambridge, eastern England, on April 25, 2024.

    JUSTIN TALLIS/AFP via Getty Images


    “It’s extremely exciting and a massive privilege actually to be able to work with the remains of any individual but especially one as special as her,” she told BBC News.

    Solecki’s discovery of a cluster of bodies with one surrounded by clumps of ancient pollen led him to controversially argue that this was evidence of funerary rituals with the dead placed on a bed of flowers.

    Political difficulties meant it took around five decades for a team from Cambridge and Liverpool John Moores universities to be allowed back to the site in the Zagros mountains of northern Iraq.

    “Skull was as flat as a pizza”

    The last Neanderthals mysteriously died out around 40,000 years ago, just a few thousand years after humans arrived.

    Shanidar Z’s skull — thought to be the best preserved Neanderthal find this century — had been flattened to a thickness of 0.7 inches, possibly by a rockfall relatively soon after she died.

    Professor Graeme Barker from Cambridge’s McDonald Institute for Archaeological Research, told the BBC the “skull was as flat as a pizza, basically.”

    BRITAIN-IRIAQ-ARCHAEOLOGY-NEANDERTHAL
    A picture shows the rebuilt skull and a physical reconstruction of the face and head, of a 75,000-year-old Neanderthal woman, named Shanidar Z, after the cave in Iraqi Kurdistan where her skull was found in 2018, at the University of Cambridge, eastern England, on April 25, 2024. 

    JUSTIN TALLIS/AFP via Getty Images


    “It’s a remarkable journey to go from that to what you see now,” Barker said. “As an archaeologist, you can sometimes get blasé about what you’re doing. But every now and then you are brought up short by the fact you are touching the past. We forget just what an extraordinary thing it is.”

    Shanidar Z is the fifth body to be identified in the cluster buried over a period of at least several hundred years right behind the rock in the center of the cave.

    Archaeologists believe the stone was used as an identifier to allow itinerant Neanderthals to return to the same spot to bury their dead.

    Latest research by team member Professor Chris Hunt of John Moores now suggests the pollen that gave rise to Solecki’s contentious “flower burial” theory might in fact have come from bees burrowing into the cave floor.

    But Hunt said there was still evidence — such as the remains of a partially paralyzed Neanderthal found by Solecki —  that the species were more empathetic than previously thought.

    “There’s been this huge reappraisal which was actually started by Ralph Solecki in this cave with ‘Shanidar 1’ with his withered arm and his arthritis and his deafness who must have been looked after. That tells us there was compassion,” he said.

    The positioning of the bodies in the cluster in the same spot, in the same position and facing in the same direction implied “tradition” and the “passing of knowledge between generations,” he said.

    “Exciting” and “terrifying” discovery

    “It looks much more like purposeful behavior that you wouldn’t associate with the text book stories about Neanderthals which is that their lives were nasty, brutish and short,” he added.

    Pomeroy, the Cambridge palaeo-anthropologist who uncovered Shanidar Z, said finding her skull and upper body had been both “exciting” and “terrifying.”

    The skeleton and the surrounding sediment had to be strengthened in situ with a glue-like consolidant before being removed in dozens of small foil-wrapped blocks.

    Lead conservator Lucia Lopez-Polin then pieced together the over 200 bits of skull as the first step in the facial reconstruction for the just-released Netflix documentary “Secrets of the Neanderthals.”

    Pomeroy said the task had been like a “high stakes 3D jigsaw puzzle” especially as the fragments were very soft “similar in consistency to a biscuit dunked in tea”.

    The rebuilt skull was then 3D-printed allowing palaeo-artists and identical twins Adrie and Alfons Kennis in The Netherlands to complete the reconstruction with layers of fabricated muscle and skin for the documentary, which was produced by the BBC Studios Science Unit.

    Pomeroy said Neanderthal skulls looked very different to those of humans “with huge brow ridges and lack of chins.”

    But she said the recreated face “suggests those differences were not so stark in life,” highlighting the interbreeding between Neanderthals and humans “to the extent that almost everyone alive today still has Neanderthal DNA.”

    The BBC reported that the researchers are confident the Neanderthal is a female. Because no pelvic bones were recovered, archaeologists relied on certain dominant proteins found in the tooth enamel that are associated with female genetics. The slight stature of the skeleton also supports the interpretation.

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