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.
Read the OPN story: biotech technology physics.
New technique creates new possibilities for synthetic biology and biotechnology.
Can we predict immunotherapy success by forecasting severe radiation-induced lymphopenia (RIL)? A pretreatment NSCLC nomogram shows only low RIL-risk patients benefit from adjuvant durvalumab, potentially enabling personalized RIL mitigation and optimized immunotherapy. Read it here in the RedJournal.
Severe radiation-induced lymphopenia (RIL) during concurrent chemoradiotherapy (CCRT) for NSCLC has been associated with poorer outcomes and reduced immunotherapy efficacy. Because RIL often develops late during CCRT, identifying patients at risk before treatment may be clinically relevant. This study aimed to develop and validate a nomogram based on pretreatment predictors for severe RIL, and secondarily to explore associations between predicted RIL risk and adjuvant durvalumab-associated survival.
“This led us to the following idea: what if instead of preventing the formation of droplets, we created conditions that would drive Tau and alpha synuclein inside the droplets toward their healthy path, discouraging them from taking the disease path?” said a co-corresponding author of the work.
The team worked with biochemical and biophysical techniques, high-resolution microscopy and neuronal-based assays to investigate tubulin’s role in modulating and preventing the formation of toxic aggregates in droplets.
The researchers show that Tubulin modulates Tau:αSyn condensates by promoting microtubule interactions and inhibiting homotypic and heterotypic pathological oligomers. Tubulin partitioning into condensates promotes microtubule polymerization and prevents Tau and αSyn oligomerization.
In the absence of Tubulin, Tau-driven condensation accelerates formation of pathogenic Tau:αSyn heterodimers and amyloid fibrils. The authors also identify distinct Tau and αSyn structural states in pathological Tubulin-absent versus physiological Tubulin-rich condensates.
“When tubulin levels are low, as it has been found in Alzheimer’s disease, microtubules are less abundant and Tau and alpha synuclein can form toxic aggregates,” the author said. “But when tubulin is present, Tau and alpha‑synuclein shift away from harmful aggregates and instead promote the assembly of healthy microtubules,” the author said. “Tubulin redirects the activity of these proteins by giving them something productive to do.” ScienceMission sciencenewshighlights.
Researchers have discovered a potential new strategy to fight back against Alzheimer’s and Parkinson’s diseases, conditions that are linked to the toxic accumulation of Tau and alpha synuclein protein clumps in the brain. The team reports in Nature Communications that tubulin, the building block of microtubules, the cell’s internal ‘railway tracks,’ can stop Tau and alpha synuclein from forming toxic clumps and instead steer them into their normal, healthy roles.
Scientists have uncovered new genetic rules that determine whether the immune system’s “killer” T cells remain powerful long-term defenders or become worn out and ineffective. By building a detailed genetic atlas of CD8 T cell states, researchers identified key molecular switches that push these cells toward either resilience or exhaustion. Remarkably, disabling just two previously unknown genes restored the tumor-killing power of exhausted T cells while preserving their ability to provide lasting immune protection.
Here, Fanghui Lu & team report OLIG2, a master transcription factor in glioblastoma stem cells, enables immune evasion by suppressing CXCL10. And, targeting OLIG2 overcomes immunotherapy resistance and improves survival.
1Department of Cancer Center, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
2Department of Neurosurgery, Key Laboratory of Major Brain Disease and Aging Research (Ministry of Education), The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
3School of Basic Medical Sciences, Chongqing Medical University, Chongqing, China.
For decades, the field of biogerontology has largely focused on a single strategy: manipulating metabolism to slow down the rate at which we age. While approaches like caloric restriction have produced fascinating results in short-lived organisms like worms and flies, they have shown clear limits in mammals. Slowing the accumulation of damage does not remove the damage that is already there. It merely delays (not prevents) the onset of disease, particularly when applied late in life.
Murphy & colleagues reported on a patient with WHIM syndrome who was cured of the disease by a spontaneous somatic genetic event that deleted the mutant CXCR4 allele in a single hematopoietic stem cell.
Here, the team now show CRISPR silencing of the Cxcr4 overactive disease allele corrects leukopenia in a murine model of WHIM syndrome, demonstrating a new therapeutic strategy for dominant immune disorders.
Molecular Signaling Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.
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.