Researchers have discovered how to guide the evolution of proteins with light to develop more complex proteins, paving the way for new possibilities in synthetic biology and biotechnology.
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New technique creates new possibilities for synthetic biology and biotechnology.
Alzheimer’s disease starts with a sticky protein called amyloid beta that builds up into plaques in the brain, setting off a chain of events that results in brain atrophy and cognitive decline. Microglia, immune cells that reside in the brain, are responsible for removing brain waste but can become dysfunctional when overwhelmed in the context of neurodegenerative disease.
To reduce the cleaning burden on microglia, first author transformed astrocytes, the most abundant cell type in the brain, into amyloid-cleaning machines. The author custom-designed and delivered a gene to astrocytes that codes for the chimeric antigen receptor (CAR) via a harmless virus injected into mice. The CAR, now present on the surface of astrocytes, enabled the cells to capture and engulf amyloid beta proteins. With their newly acquired ability, the astrocytes — generally responsible for keeping the brain tidy — concentrated their efforts on only cleaning amyloid beta plaques in mice prone to its buildup.
Mice carrying genetic mutations that increase people’s risk of developing Alzheimer’s disease develop amyloid beta plaques that saturate the brain by six months of age. The author injected two groups of mice with the virus carrying the CAR-expressing gene: young mice before they developed plaques and older mice with brains saturated with plaques, then, waited three months.
As the younger mice aged, the CAR-astrocytes prevented amyloid beta plaque development. At nearly six months of age, when untreated mice normally have brains saturated with harmful plaques, brains of treated mice were plaque-free. Meanwhile, older mice with plaque-saturated brains at the time of treatment saw a 50% reduction in the amount of amyloid beta plaques compared to mice receiving an injection of a virus lacking the CAR gene.
The researchers have filed a patent related to the approach used to engineer CAR-astrocytes.
“Consistent with the antibody drug treatments, this new CAR-astrocyte immunotherapy is more effective when given in the earlier stages of the disease,” said a co-author on the paper. “But where it differs, and where it could make a difference in clinical care, is in the single injection that successfully reduced the amount of harmful brain proteins in mice.” ScienceMission sciencenewshighlights.
A team from University of Toronto Engineering is the first to synthesize long noncoding RNA (lncRNA) outside the cell—a new approach to drug discovery that has already yielded some promising anti-inflammatory molecules. The team was inspired by advances in the field of messenger RNA (mRNA) and protein replacement therapies. They realized that a similar approach could be used to deliver lncRNA to the body, unlocking a potential new source of drugs.
“Only about 25% of our DNA encodes for proteins, including everything from insulin for regulating blood sugar to antibodies for immune defense,” says Professor Omar F. Khan, senior author on a paper published in Science Signaling that describes the new discovery.
“Proteins are made via messenger RNA, or mRNA, which conveys the instructions for how to build proteins from our genes to our ribosomes, the part of our cells where proteins are assembled.”
From frozen habitats to millennia-long journeys, we explore the science behind cryogenic arks and deep-time interstellar travel.
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/ discord Credits: Cryogenic Arks – Sleeping Through the Ages Written, Produced & Narrated by: Isaac Arthur Select imagery/video supplied by Getty Images Music by Epidemic Sound: http://nebula.tv/epidemic & Stellardrone Chapters 0:00 Intro 2:50 The Need for Cryogenic Arks 6:12 From Freezing Flesh to Preserving Life 12:33 The Physics and Engineering of the Cryogenic Ark 18:46 The Problem of Time and Identity 24:59 Oldest & Newest 25:59 How Long Can We Stay Frozen? 30:48 Crew Dynamics and Risk 35:18 Beyond Cryogenics – Slowing Time Itself.
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EPFL researchers have developed a light-based method that can produce proteins that switch states, respond to signals, and even compute, using light and the cell cycle.
Evolution is biology’s powerful method of engineering. It works by generating many variants of DNA, RNA, and proteins inside cells and letting nature “select” the organism that performs best. Early farmers started taking advantage of evolution by interfering with natural selection and letting only the most productive livestock and crops mate.
In laboratories, researchers have developed methods for directed evolution of proteins, especially enzymes and antibodies, that are used in household detergents, medicine, and industry.
Key cytoplasmic sensors, including the RNA sensors RIG-I and melanoma differentiation-associated gene 5 (MDA5), along with the DNA sensor cyclic GMP-AMP synthase (cGAS), specifically recognize viral RNA and DNA.6,7 Upon nucleic acid detection, PRR adaptors (TRIF, MAVS, and STING) recruit kinases such as TBK1 and IKKε to initiate downstream signaling cascades.8,9,10 This process leads to the phosphorylation and activation of the transcription factor interferon regulatory factor 3 (IRF3), which subsequently translocates from the cytoplasm to the nucleus to trigger type I interferon (IFN-I; IFN-α/β) expression.11,12,13 The secreted IFNs then activate pathways that culminate in the expression of interferon-stimulated genes (ISGs), establishing an antiviral state in host cells.13
Guanine nucleotide exchange factor H1 (GEF-H1), encoded by Arhgef2, is a microtubule-associated protein (MAP) and plays a pivotal role in diverse cellular processes, including epithelial barrier permeability, cell cycle regulation, cell motility, polarization, and leukemic cell differentiation.14 Beyond its structural role, GEF-H1 contributes to inflammatory cytokine production, intracellular mycobacterial elimination, and macrophage-mediated antiviral defenses.15,16 Activation of GEF-H1 enhances RLR signaling through its interaction with TBK1, thereby promoting IFN-β induction in macrophages via a microtubule-dependent mechanism.15 Its regulation also extends beyond microtubule binding and involves phosphorylation-dependent mechanisms and dynamic protein-protein interactions.17,18,19,20,21,22,23 The RhoA-specific GEF activity of GEF-H1 is inhibited by its phosphorylation at Ser886 and Ser959, which is mediated by microtubule affinity-regulating kinase 2 (MARK2).24 Notably, here, MARK2 was also screened out to interact with GEF-H1 by immunoprecipitation and mass spectrometry (IP-MS) assays in A549 cells. MARK2 belongs to the evolutionarily conserved KIN1/PAR-1/MARK family of serine/threonine kinases, which are crucial for microtubule stability and cellular polarity from yeast to humans.25 All mammalian MARK family members (MARK1–4) share a conserved architecture, featuring an N-terminal catalytic domain, a central ubiquitin-associated domain, and a C-terminal kinase-associated domain.26,27 These kinases regulate microtubule dynamics by phosphorylating key MAPs, including TAU, MAP2, and MAP4.28,29 However, their roles in viral infections remain poorly understood.30
Given the importance of phosphorylation-dependent signaling in antiviral responses, we hypothesized that MARK2 may modulate innate immunity through interacting with GEF-H1. To test this, we employed a combination of in vitro and in vivo approaches, including MS-based interactome profiling, reporter gene assays, gene editing via CRISPR-Cas9, in vitro kinase assays, viral infection models in primary macrophages and cell lines, and mouse models of RNA and DNA virus infection. By elucidating the functional significance of the MARK2-GEF-H1-TBK1 signaling axis, this study aims to reveal a previously uncharacterized layer of innate immune regulation and identify potential targets for broad-spectrum antiviral strategies.
Multiphoton microscopy is used in biomedical research to study cells and tissues. Today, so-called two-photon microscopy is used to study processes within cells, but the technique has limitations in terms of image resolution. Four-photon microscopy provides images with higher resolution. However, such instruments are very expensive and, when studying biological material, the powerful laser light required can damage samples.
“In this project, we have developed molecules to visualize molecular-level details and monitor processes using the more common two-photon microscopy technique. These molecules have the capacity to achieve higher resolution than with four-photon microscopy, although two-photon microscopy is used,” says the project coordinator Joakim Andréasson, Professor at the Department of Chemistry and Chemical Engineering at Chalmers University of Technology.
“In the long term, results from studies of this kind may provide new insights into diseases, pharmaceuticals and the very smallest building blocks of life.”
Around the world, scientists are exploring an unexpected solution to the growing data crisis: storing digital information in synthetic DNA. The idea is simple but powerful—DNA is one of the most compact, durable information systems on Earth. But one issue has held the field back. Once data is written into DNA, it can’t be changed.
Now, researchers at the University of Missouri are helping to solve that problem by transforming DNA from a one-time medium into a rewritable digital hard drive. Their research is published in the journal PNAS Nexus.
“DNA is incredible—it stores life’s blueprint in a tiny, stable package,” said Li-Qun “Andrew” Gu, a professor of chemical and biomedical engineering at Mizzou’s College of Engineering. “We wanted to see if we could store and rewrite information at the molecular level faster, simpler and more efficiently than ever before.”
Ren et al. humanize and structurally optimize a chimeric anti-SFTSV antibody, generating variants with markedly enhanced neutralization potency by strengthening binding to recombinant Gn and intact virions, providing full in vivo protection and establishing a generalizable framework for therapeutic antibody engineering.
Gene therapy has been successfully used to treat a number of diseases, including immune deficiencies, hereditary blindness, hemophilia and, recently, Huntington’s disease, a fatal neurological disorder.
An advance reported in the journal Neuron adds to the technique’s growing track record of evidence supporting the view that it could unlock powerful, personalized therapies: Rice University bioengineer Jerzy Szablowski and collaborators in Vincent Costa’s lab at Emory University found that released markers of activity (RMAs) — engineered proteins designed to cross the blood-brain barrier and persist in the blood for hours at a time, providing a reliable and noninvasive way to get information about gene expression in the brain — work just as well in monkeys as they do in mice.
On the route from laboratory discovery to lifesaving treatment, large animal model studies are a critical part of the process. Most research never reaches this stage.