Weekly Updates | Feb 18 | #3
This week, we bring you the studies that identified new targets for treatments of diseases, and the retroviral link to our brain. Also find about the unique shape of neutrophil nuclei
PANK4 AND ITS ROLE IN GLIOBLASTOMA
New research by the University of Sussex reveals that the protein PANK4 plays a crucial role in chemotherapy resistance for glioblastoma, a highly aggressive brain cancer. When PANK4 is removed, cancer cells respond better to standard chemotherapy drugs, offering potential improvements in treatment outcomes. Glioblastoma patients with high PANK4 levels exhibited lower survival rates, emphasizing the protein's significance. The findings suggest a promising avenue for drug development to reverse chemo-resistance, providing hope for enhanced treatments and increased life expectancy.
Findings:
🧠 Glioblastoma, a devastating brain cancer, affects around 3,200 adults annually in the UK and 250,000–300,000 globally, with a survival rate of 1 to 18 months post-diagnosis.
🧪 The understudied protein PANK4 obstructs cancer cells' response to chemotherapy; its removal improves cell sensitivity to the main glioblastoma treatment drug.
🩺 Following tumor removal, glioblastoma patients undergo radiation and temozolomide chemotherapy, but resistance quickly develops, limiting the drug's effectiveness.
👩🔬 Prof Georgios Giamas and an international research team at Sussex identified PANK4 as a key factor in chemo-resistance, paving the way for potential therapeutic interventions.
💊 PANK4 depletion is linked to increased cancer cell death and improved patient response to temozolomide, presenting a vulnerability that could be targeted for better treatment outcomes.
🌐 The study contributes to the University of Sussex's groundbreaking research on early glioblastoma diagnosis and treatment, with future efforts focused on developing drugs to reverse chemo-resistance.
🤝 Action Against Cancer, a funder of the research, expresses pride in supporting this groundbreaking work, offering hope for patients with aggressive brain cancer.
Reference:
New study offers hope for thousands impacted each year by aggressive brain cancer
Viviana Vella, Angeliki Ditsiou, Anna Chalari, Murat Eravci, Sarah K. Wooller, Teresa Gagliano, Cecilia Bani, Emanuela Kerschbamer, Christos Karakostas, Bin Xu, Yongchang Zhang, Frances M.G. Pearl, Gianluca Lopez, Ling Peng, Justin Stebbing, Apostolos Klinakis, Georgios Giamas. Kinome‐Wide Synthetic Lethal Screen Identifies PANK4 as a Modulator of Temozolomide Resistance in Glioblastoma. Advanced Science, 2024
NEW TARGET TO TREAT INFLAMMATORY DISEASES
Scientists from the Immunology Translational Research Programme at the Yong Loo Lin School of Medicine, National University of Singapore, and their collaborators at the Harbin Institute of Technology, China, have uncovered the atomic-level structure of the SPNS2 protein. This protein plays a crucial role in transporting S1P molecules to trigger immune cell responses in infected organs and tissues. The researchers used nanobodies to enlarge the SPNS2 structure, allowing them to observe S1P molecules through cryogenic electron microscopy. The findings offer valuable insights into how S1P molecules are released, potentially paving the way for targeted drug development to treat inflammatory diseases.
Findings:
🧬 Protein Carrier Function: SPNS2 acts as a protein carrier, transporting S1P molecules from endothelial cells to induce immune cell responses in infected organs and tissues.
🔬 Structural Analysis: Using nanobodies, scientists enlarged the SPNS2 structure, enabling the observation of S1P molecules through cryogenic electron microscopy at an atomic level.
🤿 Cryogenic Electron Microscopy: The technique allowed researchers to visualize the SPNS2 protein and its dynamic shape changes during the release of S1P signaling molecules.
🧪 Drug Development Potential: Understanding how SPNS2 releases S1P molecules provides a foundation for developing drugs that target the protein, potentially enhancing drug efficacy in treating inflammatory diseases.
🩹 Key Role in Inflammation: SPNS2 facilitates the binding of S1P signaling molecules, triggering immune cells to leave lymph nodes and induce inflammation in different body parts.
⚙️ Shape Adaptability: Composed of amino acids, the malleable SPNS2 protein can change its shape to release S1P molecules through small cavities within the protein.
🧪 Pre-clinical Models and Disease Treatment: Deleting SPNS2 protein from pre-clinical models effectively blocks the S1P signaling pathway, showing promise in treating inflammatory conditions such as multiple sclerosis.
Reference:
IS YOUR BRAIN A GIFT BY RETROVIRUSES?
Ancient viruses, specifically a retrovirus-derived genetic element known as "RetroMyelin," are found to be crucial for the evolution of myelin, a fatty tissue that surrounds nerve axons in vertebrates. Myelin facilitates rapid impulse conduction, enabling the development of complex brains and diverse vertebrates. Researchers from Altos Labs-Cambridge Institute of Science discovered RetroMyelin's role while studying gene networks in oligodendrocytes, the cells responsible for myelin production. This finding sheds light on the molecular mechanisms triggering myelin appearance and its vital role in vertebrate evolution. RetroMyelin's presence in diverse vertebrates suggests multiple retroviral invasions through convergent evolution.
Findings:
🦠 Ancient Viruses and Myelin Evolution: Retroviruses, specifically the RetroMyelin genetic element, are essential for myelin production in mammals, amphibians, and fish, indicating their role in vertebrate evolution.
🧬 Molecular Mechanisms of Myelin Appearance: Myelin, a complex fatty tissue, appeared in the tree of life around the time of jaws' evolution. The study reveals that RetroMyelin regulates the expression of myelin basic protein, a key component of myelin.
🐁 Rodent Experiments: In rodents, inhibiting RetroMyelin led to the inability of oligodendrocytes to produce myelin basic protein, highlighting the critical role of this genetic element in myelin formation.
🌐 Evolutionary Drive for Quicker Impulse Conduction: Quicker impulse conduction in axons is crucial for survival, driving the evolutionary acquisition of RetroMyelin and the development of complex brains.
🌳 Convergent Evolution of RetroMyelin: Phylogenetic analysis of 22 jawed vertebrate species reveals that RetroMyelin sequences were acquired multiple times through convergent evolution, rather than a single incorporation in the ancestor.
🐠🐸 Functional Role in Fish and Amphibians: Experimental disruption of RetroMyelin in zebrafish and frogs resulted in significantly reduced myelin production in developing fish and tadpoles, highlighting its functional role across species.
🧬🔍 Exploring Retroviruses in Evolution: The study opens a new avenue to explore how retroviruses, especially non-coding regions, play a broader role in directing evolution and physiological processes.
Reference:
HOW BIRDS LEARNT TO FLY?
Evolutionary biologists at Johns Hopkins Medicine have conducted research combining PET scans of modern pigeons with studies of dinosaur fossils to uncover the evolution of bird brains for flight. The study reveals an adaptive increase in the size of the cerebellum, a brain region responsible for movement and motor control, in some fossil vertebrates. This finding is crucial in understanding the development of flight-ready brains in birds and their dinosaur ancestors.
Findings:
🧠 Cerebellum Adaptation: The research suggests an increase in the cerebellum's size in some fossil vertebrates as a key adaptation for powered flight.
🦴 Unique Evolutionary History: Flight in vertebrates is rare, with only pterosaurs, bats, and birds having evolved to fly. Despite not being closely related, these groups share cerebellum adaptations for flight.
🕵️♀️ PET Scans and Fossil Records: The researchers used PET scans on pigeons during flight, identifying significant activity increases in the cerebellum. They linked these findings to the fossil record, connecting cerebellum volume increase to early maniraptoran dinosaurs.
🦕 Dinosaur Ancestors and Brain Complexity: The study found evidence of increased tissue folding in the cerebellum of early maniraptorans, indicating a rise in brain complexity, linking modern birds to their dinosaur ancestors.
Reference
THE FLOWER-PETAL-SHAPED NUCLEUS OF NEUTROPHILS
A groundbreaking study has unveiled the mystery behind the unique nuclear structures of neutrophils, solving a puzzle that dates back to the 1880s. Neutrophils, specialized blood cells crucial for immune system protection, possess nuclei with flower petal-like arrangements, allowing them to effectively combat invading pathogens. The research, led by University of California San Diego School of Biological Sciences, reveals the mechanism behind the assembly of these distinctive nuclear shapes. By removing chromatin loops, researchers transformed round nuclei into flower petal arrangements and activated inflammatory genes associated with the immune response. This breakthrough opens new possibilities for engineering immune cells with altered nuclear structures for enhanced disease-fighting capabilities, particularly in challenging environments like tumors.
Findings:
🌺 Distinctive Neutrophil Nuclei: Neutrophils, a type of white blood cell, have nuclei with flower petal-like structures, unlike the typical round or oval-shaped nuclei in most cells.
🔬 Research Breakthrough: University of California scientists, in collaboration with the Cleveland Clinic Foundation, deciphered the assembly mechanism of neutrophil nuclei using a combination of ancient staining procedures and advanced techniques.
🧬 Chromatin Loop Removal: The study revealed that removing chromatin loops transformed round nuclear shapes into the flower petal arrangements seen in neutrophils, activating genes associated with inflammation and immune response.
💡 Therapeutic Implications: The discovery could revolutionize immune therapy by providing a pathway to engineer immune cells with novel nuclear shapes. This opens the possibility of directing immune cells towards complex, solid environments such as tumors for more effective disease combat.
📖 Published Study: The findings were reported in the journal Nature in a study titled "Nuclear morphology is shaped by loop-extrusion programs," authored by Indumathi Patta, Maryam Zand, Lindsay Lee, and others.
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